The Role of Suppressors of Cytokine Signaling (SOCS) Proteins in Regulation of the Immune Response

11 Feb 2004 22:3 AR AR210-IY22-17.tex AR210-IY22-17.sgm LaTeX2e(2002/01/18)P1: IKH10.1146/annurev.immunol.22.091003.090312

Annu. Rev. Immunol. 2004. 22:503–29doi: 10.1146/annurev.immunol.22.091003.090312

Copyright c© 2004 by Annual Reviews. All rights reservedFirst published online as a Review in Advance on November 17, 2003

THE ROLE OF SUPPRESSORS OF CYTOKINE

SIGNALING (SOCS) PROTEINS IN REGULATION

OF THE IMMUNE RESPONSE

Warren S. Alexander and Douglas J. HiltonThe Walter and Eliza Hall Institute of Medical Research and The CooperativeResearch Center for Cellular Growth Factors, Parkville, 3052 Victoria, Australia;email: [email protected], [email protected]

Key Words SOCS proteins, negative regulation, cytokines, signal transduction,attenuation

■ Abstract Cytokines are an integral component of the adaptive and innate immuneresponses. The signaling pathways triggered by the engagement of cytokines with theirspecific cell surface receptors have been extensively studied and have provided a pro-found understanding of the intracellular machinery that translates exposure of cells tocytokine to a coordinated biological response. It has also become clear that cells haveevolved sophisticated mechanisms to prevent excessive responses to cytokines. In thisreview we focus on the suppressors of cytokine signaling (SOCS) family of cytoplas-mic proteins that completes a negative feedback loop to attenuate signal transductionfrom cytokines that act through the janus kinase/signal transducer and activator oftranscription (JAK/STAT) pathway. SOCS proteins inhibit components of the cytokinesignaling cascade via direct binding or by preventing access to the signaling complex.The SOCS proteins also appear to target signal transducers for proteasomal destruction.Analyses of genetically modified mice in which SOCS proteins are overexpressed ordeleted have established that this family of negative regulators has indispensable rolesin regulating cytokine responses in cells of the immune system as well as other tissues.Emerging evidence also suggests that disruption of SOCS expression or activity isassociated with several immune and inflammatory diseases, raising the prospect thatmanipulation of SOCS activity may provide a novel future therapeutic strategy in themanagement of immunological disorders.

INTRODUCTION

Cytokines, Receptors and the JAK/STAT Pathway

Communication between cells can occur at a variety of levels, from the intimate“pillow-talk” of cell-cell contact, to the “satellite TV” of widely acting, circulatinghormones and growth factors. Among the most numerous and functionally diverse

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504 ALEXANDER ¥ HILTON

group of cellular messengers are the cytokines (1) that bind to members of thehemopoietin receptor superfamily (2–4) and signal via the four members of theJanus kinase family (JAK1-3 and TYK2) (reviewed in 5) and the seven membersof signal transduction and activators of transcription family (STAT1-4, 5a, 5b, and6) (reviewed in 6, 7) (Figure 1).

The Importance of Maintaining a Balanced Response

Regulation of the initiation, duration, and magnitude of cytokine signaling oc-curs at multiple levels, including limiting the availability of cytokine to initiate aresponse, regulating the expression and half-life of cell surface receptor compo-nents, and controlling the duration of activation and half-life of intracellular signaltransduction machinery (Figure 1). Conceptually, one of the simplest means ofattenuating a response is via a negative feedback loop. This review focuses on thephysiological role of an important class of negative feedback inhibitors of signaltransduction, SOCS proteins, with particular emphasis on the immune system.

SUPPRESSORS OF CYTOKINE SIGNALING

The SOCS Protein Family

There are eight members of the SOCS protein family: the cytokine-inducible SH2domain-containing protein (CIS) and SOCS1 through SOCS7 (8–13). In addition toa central SH2 domain, the eight SOCS proteins contain a conserved and previouslyundescribed C-terminal motif that is termed the SOCS box (Figure 2) (9) thatwas also found in three other novel protein families and known as the ankyrinrepeat-containing proteins with a SOCS box (ASBs), SPRY domain-containingproteins with a SOCS box (SSBs), and WD40 repeat-containing proteins with aSOCS box (WSBs), as well as other miscellaneous proteins (13, 14). Since theiridentification, the different SOCS proteins have enjoyed a host of aliases (Figure 2);however, the SOCS nomenclature has now gained widespread, if not universal,acceptance.

Basic Principles Elucidated from In Vitro Studies

A plethora of studies have shown that SOCS1, SOCS2, SOCS3, and CIS mRNAand protein are generally present at low levels in unstimulated cells, perhaps be-cause of active repression (15–17), and that mRNA and protein levels are inducedrapidly in response to cytokines, with the STATs playing an important part inregulating SOCS gene transcription (17–25). Agents other than cytokines, for ex-ample pathogens and their products such as LPS, also induce SOCS expression(26–31). Because overexpression of SOCS proteins can inhibit signaling by a va-riety of cytokines that act via the JAK/STAT pathway, it has been proposed thatSOCS proteins may act as part of a negative feedback loop and may be induced

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SOCS PROTEINS AND THE IMMUNE RESPONSE 505

by one stimulus to inhibit a cell’s response to subsequent stimuli (Figures 3and 4).

In the case of SOCS1 there is good evidence that the SH2 domain interactswith a key regulatory tyrosine in the activation loop of JAKs (10, 32–34), whereasfor SOCS2, SOCS3, and CIS the evidence points to phosphotyrosines in the cy-toplasmic domains of cytokine receptors being the primary site of interaction (8,21, 35–56). For SOCS1 and SOCS3, an N-terminal domain, known as the kinaseinhibitory region (KIR), has also been hypothesized to contribute to negative reg-ulation by acting as a pseudosubstrate for JAKs and by increasing the strength ofthe interaction between SOCS and the signal transduction complex (32, 34, 57).Finally, there is now increasingly good evidence that the SOCS box, present at theC terminus of all SOCS proteins, acts to couple the substrate-specific interactionsof the SH2 domains to generic components of the ubiquitin ligation machinery.This leads to the polyubiquitylation of key signaling proteins, their degradation inthe proteasome, and the termination of signaling (14, 58–63).

THE PHYSIOLOGY OF SOCS FUNCTION

Because the SOCS proteins inhibit cytokine signaling via a negative feedbackloop, it was envisaged that the specific biological actions of the SOCS proteinswould emerge from an understanding of the specific cell types and cytokinesthat induce each SOCS. However, as discussed above, SOCS proteins appear tobe induced in many cell types by a multitude of different cytokines. Moreover,enforced expression of these SOCS proteins in cell culture models has resulted ina remarkably promiscuous range of activity (reviewed in 64–66). Thus, althoughoverexpression studies have provided valuable insights into the mechanisms ofSOCS action, the breadth of SOCS activity in these systems is likely to exaggeratethe physiological roles of these regulators in vivo. Over recent years, productionof transgenic mice expressing various SOCS proteins has focused attention on thein vivo actions of these proteins, and the indispensable physiological roles of SOCShave been revealed in studies of mice genetically engineered to lack functionalSocsgenes (Table 1).

We focus below on the data gleaned from analyses of genetically modified micein which SOCS activity has been enhanced or ablated, particularly where pheno-types affecting the immune system have ensued. These studies have establishedthat SOCS proteins are important biological regulators in adaptive and innate im-mune responses. In several instances, key physiological roles of individual SOCSproteins have clearly and definitively emerged from these studies, such as the in-dispensable role for SOCS1 in regulating IFNγ signaling and T cell homeostasis.In other areas, it is clear that no consensus has yet become apparent. For exam-ple, in T helper cell development, SOCS1, SOCS3, CIS, and SOCS5 all appearto be differentially expressed in Th1 versus Th2 cells, and conflicting evidenceexists regarding the specific roles for these SOCS proteins in the regulation of Th

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TABLE 1 Major phenotypic consequences of SOCS gene manipulation in vivo

Gene Knockout mice Transgenic mice

CIS Reported to have no abnormalities (96). Low body weight; lactation failure;fewer splenicγ δT, NK, andNKT cells; preferential Th2differentiation–reduced IL-2signaling (109). Anomalous T cellreceptor responses (110).

SOCS1 Neonatal lethality with fatty degeneration Suppressed signaling by severalof the liver, hematopoietic infiltration of cytokines, T cell developmentalmultiple organs, lymphopenia, apoptosis defects including increased inin lymphoid organs, and aberrant T-cell CD4+ cells, fewerγ δT cells andactivation (67, 68). Lethality due to spontaneous T cell activation (87).deregulated responses to IFNγ (72, 74),but responses toγ c receptor-dependentcytokines as well as IL-12, TNFα,LPS, insulin, and prolactin also altered(30, 31, 67, 69, 81, 83).

SOCS2 Gigantism with evidence of deregulated Gigantism with evidence ofGH signaling (111). deregulated GH signaling (56).

SOCS3 Midgestational embryonic lethality due Embryonic lethality with anemia (96).to placental insufficiency (96, 97, 99).Deregulated responses to LIF (placenta)and IL-6 (macrophages and liver)(99–102).

SOCS5 Disrupted Th2 cell responses.Attenuated IL-4 signaling (107).

SOCS6 Mild growth retardation (138).

IFNγ , interferon gamma; GH, growth hormone; IL, interleukin; LIF, leukemia inhibitory factor; Th2, T helper cell type 2;TNF, tumor necrosis factor; LPS, lipopolysaccharide;γ c, common gamma chain.

polarization in vivo. In cases such as these, it seems likely that analyses of genet-ically modified mice in which multiple SOCS proteins have been ablated, as wellas complementary studies of SOCS in human health and disease, will ultimatelybe required to delineate the precise roles of specific SOCS proteins in compleximmune cell physiology.

SOCS1 is a Key Regulator of Interferon-γ Signaling

Mice lacking theSocs1gene die within the first three weeks of life, displayinglow body weight and complex pathology (67, 68). SickSocs1−/−mice have majorliver damage, with parenchymal cells showing marked accumulation of lipid andconsequent fatty degeneration and necrosis that can affect large areas of the organ.

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Diseased livers also exhibited significant hematopoietic infiltration, characterizedby the presence of aggregates of granulocytes, eosinophils, and macrophages. InmostSocs1−/− mice, monocytic invasion of the pancreas, heart, and lungs wasalso evident (68). Analyses ofSocs1−/−mice have suggested they have defects inregulation of signaling in response to prolactin and insulin (69, 70); however, themost striking defects in these mice are found in the acquired and innate immunesystems, as discussed below.

Analysis of peripheral blood inSocs1−/− mice revealed modest reductions inhematocrit and circulating eosinophil and platelet numbers, and a variable increasein neutrophils, but most strikingly, a consistent and marked reduction in bloodlymphocytes (68). A relative deficit in lymphocytes was also evident in the spleen,in which lymphoid follicles were often absent or rudimentary and composed ofimmature cells. The thymus was markedly reduced in size in sickSocs1−/−mice,reflecting a progressive depletion of cortical thymocytes with declining health, andlymph nodes and Peyer’s patches were similarly hypocellular (67, 68). Increasednumbers of apoptotic cells were observed in the thymus and spleen of mice lackingSOCS1, accompanied by increased expression of the Bax protein, suggesting thatthe lymphopenia in these mice may be associated with accelerated apoptosis (67).Flow cytometric analysis of B-lymphoid populations revealed relatively normalnumbers of pro-B cells inSocs1−/− mice but severe deficiencies in pre-B and Blymphocytes (67, 68). The deficiency in T lymphocyte numbers in the thymus wasaccompanied by a reduction in the ratio of mature (CD3+) CD4:CD8 cells, duepredominantly to elevated numbers of CD8+ T lymphocytes, and this altered ratiowas also evident in the peripheral lymphoid organs (71). T cells inSocs1−/−micealso displayed features of activation: increased cell size and expression of elevatedlevels of activation markers including CD44, CD25, and CD69 (72).

The similarities in the pathology of sickSocs1−/− mice to that observed inwild-type mice administered with interferon (IFN) (73) led to the hypothesis thatthe disease developing inSocs1−/− mice might be due to excessive responses toIFN. Consistent with this notion,Socs1−/−mice displayed evidence of an ongoingresponse to IFNγ including constitutive activation of STAT1, the primary STATthat mediates IFNγ signaling, in the liver, and markedly elevated expression ofIFNγ -inducible genes in several SOCS1-deficient tissues (74). Direct evidencethat IFNγ is required for the development of lethal disease inSocs1−/− miceemerged when these mice were treated from birth with neutralizing antibodies toIFNγ . At three weeks of age, when all untreatedSocs1−/− mice had succumbedto lethal disease, anti-IFNγ -treatedSocs1−/− mice remained in good health anddisplayed only minor histopathological or hematological signs of disease (74). Thenecessity for IFNγ in Socs1−/− disease was unequivocally demonstrated whendouble knockoutSocs1−/− Ifng−/− mice were generated. These mice remainedhealthy and showed none of the histological features of typicalSocs1−/− disease(72, 74). Interestingly,Ifng gene dosage is a critical determinant of disease inSOCS1-deficient mice. Whereas the absence of SOCS1 leads to neonatal lethalityin the presence of two functionalIfng alleles but is tolerated without apparent

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disease in the absence of IFNγ , Socs1−/−mice with a single functionalIfng alleledevelop disease as young adult mice. Intriguingly,Socs1−/− Ifng+/− mice, whichtypically die between 30 and 70 days of age, do not simply develop an attenuatedform of the neonatal disease that characterizesSocs1−/− Ifng+/+mice, but displaya distinct pathology dominated by myocarditis and polymyositis (75). Extensiveinfiltrates involving T lymphocytes, macrophages, and eosinophils were evidentin all muscles, the heart and the cornea, with minimal involvement of other organsor tissues. Although slightly excessive numbers of hematopoietic cells were oftenobserved in the livers ofSocs1−/− Ifng+/− mice, the fatty degeneration typicalof Socs1−/− neonatal liver disease was absent. It is noteworthy that the reducedCD4:CD8 T cell ratio and excessive T cell activation associated with SOCS1-deficient mice were also clearly evident in lymphoid organs ofSocs1−/− Ifng+/−andSocs1−/− Ifng−/− animals (75), and these mice have been exploited to investigatethe basis of these T cell anomalies (see below).

Although elevated circulating concentrations of IFNγ have been observed insome mice lacking SOCS1 (72, 74), increased sensitivity of SOCS1-deficient tis-sues to IFNγ clearly plays a significant role inSocs1−/− disease. Hematopoi-etic progenitor cells committed to production of granulocytes and macrophagesfrom the bone marrow ofSocs1−/− mice exhibited hypersusceptibility to IFNγ -mediated inhibition of proliferation in vitro (76). Similarly, macrophages derivedfrom Socs1−/− bone marrow proved capable of eliminating intracellularLeish-mania majorparasites following stimulation with IFNγ at a concentration twoorders of magnitude lower than required by wild-type cells (74). SOCS1-deficientmice also displayed marked hypersensitivity to IFNγ in vivo. Administration ofIFNγ to neonatalSocs1−/− Ifng−/− mice was acutely toxic and recapitulated thepathology evident inSocs1−/−mice, at doses tolerated without symptoms in wild-type neonates (77). Consistent with hyper-responsiveness to IFNγ , Socs1−/−micealso showed increased resistance to infection with Semliki Forest virus, survivinginfectious doses lethal to wild-type mice (74).

The role of SOCS1 in attenuating IFNγ signaling has also been scrutinized atthe biochemical level. The actions of IFNγ in cells are largely mediated via thephosphorylation and activation of STAT1. Following injection of IFNγ , STAT1phosphorylation in the livers ofSocs1+/+ mice is evident within 15 min and re-mains prominent for approximately 2 h before declining to undetectable levels. Incontrast, while STAT1 phosphorylation is induced to a similar absolute level inSOCS1-deficient livers following injection of IFNγ , the phosphorylated proteinpersists and remains detectable 8 h after cytokine administration (77). Prolongedactivation of the IFNγ signaling pathway is also evident in isolated hepatocytesin vitro and can be demonstrated not only by extended phosphorylation of STAT1following IFNγ stimulation but also by the prolonged presence of activated, DNA-binding STAT1 complexes in the nuclei of these cells (77).

Together, these biological and biochemical data clearly establish that SOCS1 isa key physiological negative regulator of IFNγ signaling. The actions of SOCS1are necessary to attenuate the duration of IFNγ signaling in cells, allowing the

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beneficial immunological effects of IFNγ , but preventing the pathological conse-quences of uncontrolled responses to this inflammatory cytokine.

Immune Cells in Socs1−/−Disease

A significant reduction in the numbers of maturing B cells is a feature ofSocs1−/−

mice. However, production of SOCS1-deficient B cells is not intrinsically defectivebecause in vitro development of mature B cells from purifiedSocs1−/− precursorswas as efficient as that observed from wild-type cells (68). There is little evidencefor a direct role for B cells inSocs1−/− disease, and the loss of mature B cellsin Socs1−/− mice is likely to reflect the sensitivity of these cells to the cytotoxicactions of IFNγ (78). In contrast, T lymphocytes appear to play a crucial role inthe development of disease in mice lacking SOCS1. Transplantation of bone mar-row cells fromSocs1−/− mice into JAK3- or RAG2-deficient mice, which allowsdonor lymphoid reconstitution amid a background of host myelopoiesis, resultedin lethality of the reconstituted animals and was accompanied by expression of anactivated phenotype by donor SOCS1-deficient T cells (67, 72). WhenSocs1−/−

mice were crossed with RAG2-deficient animals, perinatal disease was eliminatedin Socs1−/−Rag2−/− double knockout mice. Thus, the capacity to generate matureT cells appears necessary for the neonatal disease inSocs1−/−mice (72) and mayreflect the fact that T cells are the primary cellular source of IFNγ .

SOCS1 has been shown to coprecipitate with the CD8/ζ and Syk components ofthe T cell receptor (TCR) signaling cascade, and overexpression of SOCS1 blocksthis pathway in a model of reconstituted TCR signaling in heterologous cells(79). The role of the T cell antigen receptor inSocs1−/− disease has been furtherexamined using transgenic mice in which T cells exclusively express specificityfor an exogenous, foreign antigen. To determine whether the T cell activationand/or the disease that develops in the absence of SOCS1 is driven by antigenstimulation,Socs1−/− mice were bred with OT-I MHC class I-restricted TCRtransgenic mice. These transgenic mice express chicken ovalbumin (OVA)-specificTCRs on CD8+ T cells; in the absence of administered OVA all these cells shouldbe na¨ıve. Untreated OT-ISocs1−/− Rag1−/− mice, in which all CD8+ T cellsare antigen-na¨ıve, survive the neonatal period but succumb to a disease in earlyadulthood resembling that inSocs1−/− Ifng+/− mice (71). Significantly, CD8+

T cells in these mice exhibited a blast-like activated morphology and expressedhigh levels of the CD44 activation marker. Similarly,Socs1−/− mice on an OT-II transgenic background, in which MHC class II–restricted OVA-specific CD4+

T cells are generated, displayed a similar lifespan and phenotype to OT-ISocs1−/−

mice. The abrogation of neonatal disease in OT-ISocs1−/− and OT-II Socs1−/−

mice argues that high-affinity TCR interaction contributes to this inflammatorysyndrome.

However, the fact that the TCR transgenicSocs1−/− mice do ultimately suc-cumb to disease in young adulthood is in clear contrast toSocs1−/−Rag1−/−mice,which remain healthy for this period (71). The difference between these models

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is the presence of T and NKT cells in the TCR transgenicSocs1−/− mice, and itimplies that SOCS1-deficient T and/or NKT cells can contribute to inflammatorydisease in a manner distinct from classical TCR-mediated autoimmunity. Hepaticlymphocytes fromSocs1−/− mice are cytotoxic for syngeneic wild-type hepato-cytes, and cell-depletion experiments suggest that this activity resides within theNKT cell population (80). The number of hepatic NKT cells was shown to besignificantly elevated inSocs1−/−mice compared with wild-type controls and se-lective stimulation of NKT cells in vivo accelerated liver disease in these animals(80).

Whereas IFNγ appears to be the pivotal player in development of liver degen-eration inSocs1−/−mice, primarily via hypersensitivity of cytotoxic hepatic NKTcells to IFNγ stimulation, several other cytokines appear likely to contribute todisease. Administration of IL-4 prior to disease inSocs1−/− mice, in combina-tion with IFNγ , accelerated liver disease in an NKT-cell dependent manner andprolonged activation of STAT6, through which IL-4 signals, has been observed inSocs1−/− cells treated with IL-4 (67). Moreover, double knockout mice lackingSOCS1 in addition to STAT6 were rescued from neonatal lethality (80). Similarly,mice lacking both SOCS1 and STAT4, through which IL-12 and IL-23 signal,show prolonged survival, and IL-12-stimulated T cell proliferation and NK cellcytotoxicity are enhanced inSocs1−/− cells (81). Thus, hypersensitivity to IL-12and/or IL-23 may also contribute to neonatalSocs1−/− disease, possibly via IL-12-stimulated increases in IFNγ production. Finally, hypersensitivity to tumornecrosis factorα (TNFα) has also been reported inSocs1−/− cells (82, 83), andit has been proposed that the apoptosis observed in tissues of neonatalSocs1−/−

mice might, at least in part, result from IFNγ -induced TNFα production (83).Although the evidence supporting a key role for T and NKT cells inSocs1−/−

pathology is compelling, the absence of SOCS1 in these cells is not in itself suf-ficient to cause disease. Mice in which theSocs1gene can be deleted in specifictissues have been created using loxP-cre recombinase technology. While the inac-tivation of theSocs1gene specifically throughout the T and NKT compartmentswas sufficient to invoke the activated T cell phenotype typical ofSocs1−/−models,disease did not develop in these mice, at least within the first 6 months of life (84).In contrast, upon transplantation of bone marrow cells fromSocs1−/− mice intorecipients in which endogenous hematopoiesis has been ablated by irradiation,disease develops but exhibits hallmarks of classical graft-versus-host disease andlacks the fatty degeneration of the liver or extensive infiltration of muscles thattypify neonatal or adultSocs1−/− disease (85). The implication of these observa-tions is that the absence of SOCS1 in target tissues as well as in T, NK, or otherhematopoietic cells that contribute to disease, is required to achieve the extensiveinflammatory lesions typical ofSocs1−/− mice. It is already well established thatthe neonatal liver is acutely sensitive to IFNγ (73) and it seems feasible that theabsence of SOCS1 in other tissues such as the pancreas, heart, and skeletal mus-cles might confer hypersensitivity to cytokines that promote a local inflammatoryresponse.

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SOCS1 and the Regulation of T Cell Homeostasis

It has emerged that SOCS1 also has important IFNγ -independent roles in T lym-phoid development and function. As previously discussed, SOCS1 is expressed athigh levels in the thymus and, in contrast to the usual pattern of SOCS1 expression,this does not appear to depend on stimulation of thymocytes with T cell cytokinesor the TCR (72). TheSocs1gene appears to be transcribed in cells at all majorstages of T cell development in the thymus (86), although there is evidence thatexpression is downregulated during immature T cell development and becomesparticularly high in double positive CD4+ CD8+ thymocytes (84, 86). Studies intransgenic mice in which SOCS1 expression was targeted to T lymphocytes pro-vided in vivo confirmation that enforced SOCS1 expression results in inhibitionof signaling by multiple T cell cytokines, including IFNγ , IL-6, and cytokinesthat act via the common gamma (γ c) receptor chain, such as IL-4 and IL-7 (87).Moreover, these mice exhibited reduced numbers of thymocytes resulting from apartial blockade in early thymocyte development (87). These observations wereconfirmed upon constitutive retroviral-mediated expression of SOCS1 in primi-tive hematopoietic cells. Enforced expression of SOCS1 suppressed expansion oflymphoid progenitors beyond the earliest pre-TCR stages of development, but didnot appear to interfere with the T cell differentiation program (86). These studiesimply that high levels of SOCS1 expression at various stages of T lymphocytedevelopment may maintain cells in a cytokine-refractory state until they receivethe appropriate developmental cues to proliferate and differentiate in an orderlyand controlled manner.

Several of the T cell anomalies that characterizeSocs1−/− disease were alsoevident in healthy mice lacking both SOCS1 and IFNγ . The reduced CD4:CD8T cell ratio in the developing thymus was prominent from an early age inSocs1−/−

Ifng−/− mice. Adoptive transfer studies demonstrated that this anomaly was cell-intrinsic, and fetal thymic organ cultures confirmed that the altered CD4:CD8 ratiooriginated in the thymus and resulted from increased production of CD8+ cells(71). Consistent with an intrinsic origin of this abnormality, a similarly reducedCD4:CD8 ratio was observed in mice in which SOCS1 was specifically deletedin T cells (84). T cells in healthySocs1−/− Ifng−/− mice also displayed increasedexpression of activation markers such as CD44, which was most profound inperipheral CD8+ cells (71). Analysis of other cell surface markers revealed thatthese cells expressed a phenotype most similar to memory T cells (71, 84). Again,this phenotype was prominent in mice in which only T cells lack SOCS1 (84), but itwas not evident in fetal thymic organ cultures, suggesting that factors external to thethymus are involved (71). Specific high-affinity stimulation of the TCR appears notto be required for expression of this activated T cell phenotype becauseSocs1−/−

mice in which CD8+ T cells express an ovalbumin-specific TCR also exhibit thisphenotype in the absence of antigen (71). Functional analysis of T cells fromSocs1−/− Ifng−/−mice revealed no apparent difference in cell survival or cytotoxicactivity compared with cells expressing SOCS1 (71). However, transplantation

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studies showed that SOCS1-deficient CD8+ T cells have an increased proliferativecapacity (71).

Because the altered balance of CD4 versus CD8 T cell development and theunusual prominence of cells with a memory T cell–like phenotype appear indepen-dent of exogenous antigen-stimulation and are evident in healthySocs1−/− Ifng−/−

mice, they cannot simply arise in response to autoimmunity or other aspects ofdisease in the absence of SOCS1, but must reflect in vivo actions of SOCS1 thatare independent of its role in IFNγ signaling. Since the phenotype ofSocs1−/−

T cells resembles in many aspects T cells undergoing homeostatic proliferation(88), it is feasible that this process is deregulated inSocs1−/− mice and that animportant role of SOCS1 is to regulate cytokines involved in T cell homeostasis. Inthis context, the cytokines that signal through the common gamma chain receptorhave been closely examined. Expression of SOCS1 is potently induced in T cellsstimulated with IL-2, IL-4, IL-7, or IL-15 (33, 89), and overexpression of SOCS1can inhibit responses to several of these cytokines (33, 86, 87, 90). T cells lackingSOCS1 exhibited hypersensitivity to signals from cytokines that act throughγ c,with activation of STAT5 evident following stimulation with significantly lowerconcentrations of IL-7 in thymocytes and each of IL-2, IL-7, and IL-15 in peripheralT cells than was observed in wild-type cells (84, 89). Moreover, in vitro, purifiedSOCS1-deficient CD4+CD8lo cells exhibited significantly increased IL-7-induceddifferentiation to CD8+ single positive cells relative to wild-type controls, and thiswas amplified when IL-7 was combined with IL-2 and IL-15 (84). Proliferativeresponses of peripheral CD8+ T cells fromSocs1−/− Ifng−/− mice also revealedhypersensitivity to IL-2 and IL-4 (89). Similarly, upregulation of CD44 expres-sion on sorted populations of CD44lo cells from mice lacking SOCS1 revealed thatwhereas only minor changes were induced by cytokine signaling through theγ creceptor in wild-type cells, robust induction of CD44 was evident inSocs1−/− cells,particularly in IL-2-stimulated peripheral T cells and IL-7-stimulated thymocytes(71, 84). Together, these data reveal that increased sensitivity to signals fromγ c-dependent cytokines correlates with changes inSocs1−/− T cells in vitro that aresimilar to those observed in SOCS1-deficient mice in vivo and provide compellingevidence that SOCS1 is an important regulator of this family of cytokines.

Although Socs1−/− Ifng−/− mice survive the lethal neonatal and young adultinflammatory diseases typical ofSocs1−/− Ifng+/+andSocs1−/− Ifng+/−mice, laterin life they succumb to a range of diseases including chronic inflammatory lesions,polycystic kidneys, and pneumonia (91). Thus, the IFNγ -independent actions ofSOCS1 are essential for continued health of the animal, and it is tempting tohypothesize that control of the immune system via regulation ofγ c-dependentcytokines is also an important function of SOCS1 throughout life.

SOCS1 has also been implicated in T helper cell development. Differentiationof naı̈ve CD4+ T cells into Th1 cells has been correlated with expression of highlevels of SOCS1 (92). However, na¨ıveSocs1+/− CD4+ cells underwent enhanceddifferentiation in vitro under either Th1- or Th2-polarizing conditions (93). En-hanced in vivo polarization was also evident inSocs1+/− mice upon infection

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with Listeria monocytogenes, which induces Th1 responses as well as followinginoculation withNeobythitis braziliensis, an inducer of Th2 differentiation (93).In contrast, unlike the enhanced Th1 response observed followingL. monocyto-genesinfection (93), in response to intradermal infection withLeishmania major,Socs1+/− mice developed a normal Th1 response and controlled parasitemia in amanner indistinguishable to that of wild-type mice. In this model, skin lesions andlymphadenopathy persisted inSocs1+/− mice, suggesting that other anomalies inthe SOCS1-deficient immune system might promote increased tissue damage inresponse to infection (94). An additional study has suggested a role for IL-6in preventing Th1 differentiation via stimulation of SOCS1 and the subsequentblockade of IFNγ signal transduction (95). Thus, although evidence is mountingthat SOCS1 may be involved in T helper cell differentiation, a consistent modelhas not yet emerged for a specific role in Th polarization, and further studies willbe needed to clarify whether SOCS1 contributes to this process in vivo.

The Role of SOCS3 in the Immune System

The deletion ofSocs3by gene targeting resulted in embryonic lethality at midges-tation (96, 97) because of defects in the structure of the placenta that may be due todysregulated LIF signaling (98, 99), rather than defects in erythropoiesis, as firstsuggested (96).

The lethal phenotype inSocs3−/− mice has frustrated efforts to define the keyphysiological roles of SOCS3 in adult tissues, including the immune system. How-ever, recent exploitation of conditional gene targeting technology as well as studiesof adult recipients ofSocs3−/− fetal liver transplants has begun to overcome thisobstacle. Mice in which the coding sequence of theSocs3gene has been specifi-cally deleted in the liver or in macrophages have been produced, and analysis hasrevealed a key role for SOCS3 in the regulation of IL-6 signaling. In mice bear-ing SOCS3-deficient livers, injection of IL-6 led to prolonged activation of bothSTAT3 and STAT1 relative to that observed in wild-type livers (100). Similarly, inmacrophages lacking SOCS3, enhanced IL-6-induced STAT3 and STAT1 (100–102) as well as SHP2 activation (102) were also observed. Prolonged biochemicalresponses to IL-6 correlated with increased sensitivity ofSocs3−/− macrophagesto the inhibitory effects of IL-6 on proliferation (100).

Although enforced expression of SOCS3 can inhibit responses to IFNγ (103),the regulation of IFNγ signaling was unperturbed in livers lacking SOCS3: Thekinetics and magnitude of IFNγ -induced STAT1 activation in SOCS3-deficientlivers were indistinguishable from those in wild-type livers (100). Thus, responsesto IL-6 and IFNγ in SOCS3-deficient livers are the reciprocal of that observedin Socs1−/− tissue, where prolonged responses to IFNγ , but not IL-6, prevail(77, 100). Although SOCS1 and SOCS3 are both induced by IL-6 and IFNγ ,and are capable of inhibiting responses to these cytokines when overexpressed,in vivo the actions of these SOCS proteins are not interchangeable but specific andreciprocal.

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Analysis of cytokine-responsive genes in IL-6-stimulated cells revealed thatwhereas expression of a number of genes was induced as anticipated in wild-typelivers or macrophages, the expression of a significantly larger group was stimulatedin IL-6-treatedSocs3−/− cells. Intriguingly, many of these additional genes are notnormally associated with IL-6 responses, but are typically induced upon exposureof cells to IFNγ (100, 102) and may reflect prolonged activation of STAT1 byIL-6 in the absence of SOCS3. Previous studies have shown a similar IFNγ -likeresponse in STAT3-null cells exposed to IL-6 (104). Because SOCS3 expressionappears to be STAT3-dependent (25), it follows that the altered response to IL-6observed in STAT3-deficient cells occurs because these cells are unable to induceSOCS3. Together, these data indicate that SOCS proteins can influence the qualityas well as quantity of cellular responses to cytokines. They raise the possibilitythat significant overlap exists between the signaling pathways triggered by IL-6and IFNγ and that a key role for SOCS3 is to sculpt the specific response observedin cells exposed to IL-6, perhaps particularly by restricting activation of STAT1.

In addition to IL-6, IL-10 and LPS also potently induce expression of SOCS3.However, inSocs3−/−macrophages, LPS- and IL-10-induced responses were nor-mal, suggesting that SOCS3 is not a physiological regulator of the signaling cas-cades initiated by these agents (101, 102). However, the altered qualitative responseto IL-6 in Socs3−/− cells was also evident when responses of SOCS3-deficientmacrophages to IL-6 and IL-10 were compared. Whereas LPS-induced inductionof inflammatory cytokine production by macrophages is normally inhibited by IL-10 and unaffected by exposure to IL-6, inSocs3−/−macrophages, IL-6 mimickedIL-10 with potent inhibition of LPS-induced IL-12 and TNFα production (101).

Like SOCS1, SOCS3 is expressed in na¨ıve T cells. However, in contrast toSOCS1, which is associated with differentiation to Th1 cells, SOCS3 becomesprominently expressed in the Th2 class of helper T lymphocytes (92, 105–107).Transgenic mice in which SOCS3 is constitutively expressed in T cells are healthybut show a reduced proliferative response to T cell mitogens (106). TCR-mediatedsignaling appeared to be intact inSocs3transgenic T cells, but a defect in theaugmentation of IL-2 production and NF-κB activation by CD28 costimulationof anti-TCR-activated T cells was evident (106). Conversely, inSocs3+/− mice,CD28-mediated IL-2 production was enhanced relative to wild-type controls (106).This pattern of observations was reproduced using a differentiated Th2 cell linein which SOCS3 was overexpressed or inhibited by antisense RNA expression.In this model, SOCS3 levels also inversely correlated with cellular proliferationand CD28-mediated cytokine production (105). Biochemical analysis revealedthat SOCS3, via its SH2 domain, specifically binds to the phosphorylated formof CD28. Interestingly, unlike the requirement for the N-terminal KIR region ofSOCS3 for effective interaction with many cytokine receptors (see above), thisdomain appeared dispensable for the interaction of SOCS3 with CD28 (106). Al-though no specific tyrosine on the CD28 protein appeared to mediate interactionwith SOCS3, some evidence suggests that SOCS3 inhibits the association of CD28with PI3 kinase, which is known to require Tyr-189 on CD28 for recruitment to the

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complex (106). Together these data suggest a model in which SOCS3 contributesto maintaining quiescence in T lymphocytes and that antigen-stimulated downreg-ulation of SOCS3 expression allows T-helper cell activation. SOCS3 appears tohave an important supplementary role in controlling CD28-mediated responses indifferentiated Th2 cells. However, it should be noted that T cell development wasreported to be unaffected in adult mice reconstituted with blood cells fromSocs3−/−

fetal liver stem cells (96). The imminent availability of mice in which theSocs3gene has specifically been deleted in T cells will help clarify the nonredundantroles of SOCS3 in T lymphopoiesis.

The Physiological Actions of Other SOCS Family Members

Widespread expression of CIS in transgenic mice resulted in a panoply of pheno-types including growth retardation and a failure to lactate, which closely resembledabnormalities evident in mice lacking STAT5a and/or STAT5b (108, 109). Thus,these observations suggested a particular role for CIS in regulating responses tocytokines that signal via STAT5. Indeed, T cells from CIS transgenic mice wererefractory to the effects of IL-2: A failure to activate STAT5 was observed andproliferative responses were attenuated (109). Constitutive expression of CIS inthe spleen and the thymus resulted in a significant reduction in the number ofγ δ

T cells, NK and NKT cells, and T cells from these mice exhibited a tendency forTh2 polarized differentiation in vitro (109). Again, similar immune phenotypesare evident in mice lacking STAT5, and although the specific cytokine signalingpathways have not been defined, it is likely that blockade of STAT5-mediated cy-tokine responses in CIS transgenic mice accounts for these immune cell anomalies.Curiously, in an independent study of cells from transgenic mice expressing CIS inCD4+ T cells, enhanced TCR-mediated proliferation and survival, cytokine pro-duction, and superantigen-mediated T cell activation were observed in vitro (110).Phosphorylation of ZAP-70, an immediate post-TCR signaling event, appeared tooccur normally in CIS transgenic CD4+ cells, but enhanced activation of MAPkinases was evident and interaction of CIS with PKCθ was observed (110). Theauthors propose that via regulation of PKCθ , CIS modulates signals transmittedfrom TCR activation to the MAP kinases (110). Nevertheless, T cell developmentappeared to occur normally in these CD4+ CIS transgenic mice and so the bio-logical consequences of these observations are unclear. T cell development is alsoreportedly normal in mice in which the gene encoding CIS has been inactivated(96). Thus, whereas CIS clearly has profound effects on enforced expression inimmune cells, its precise physiological role remains obscure.

The complexity of the contribution of SOCS proteins to T cell regulation isfurther illustrated by an apparent role for SOCS5 in regulation of IL-4 signal-ing and Th2 cell differentiation. SOCS5 appears to be preferentially expressed inTh1 cells and could coprecipitate with the Box1 region of the IL-4 receptor inextracts from these cells (107). SOCS5 coprecipitates with the IL-4 receptor in aphosphorylation-independent manner, and consistent with this observation, the N-terminal 50 amino acids and not the SH2 domain of SOCS5 appear to mediate the

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interaction. These observations have led to the proposal that SOCS5 inhibits IL-4signaling by precluding association of JAK1 with the IL-4 receptor. In support ofthis model, high levels of SOCS5 attenuated IL-4-induced STAT6 phosphorylationin cell lines, and comparison of T cells from transgenic mice expressing SOCS5with wild-type controls revealed reduced Th2 cell development and reduced pro-duction of the Th2 cytokines IL-4, IL-5, and IL-10 (107).

Finally, mice lacking SOCS2 exhibit increased growth in a pattern characteristicof deregulated growth hormone (GH) signaling (111).Socs2−/− cells displayedmoderately prolonged activation of STAT5, and the enhancement of growth in theabsence of SOCS2 was substantially attenuated in mice also lacking STAT5b (112).Counterintuitively, transgenic mice with widespread overexpression of SOCS2 donot show reduced growth, but exhibit a gigantism similar to mice lacking SOCS2(56). Thus, it appears that SOCS2 can both positively and negatively regulate GHsignaling, an observation that has also been made in vitro (113). SOCS2 has beenshown to interact with the GH receptor and may do so at multiple sites withinthe intracellular domain (56). As discussed above, one model for the dual activityof SOCS2 in GH regulation invokes that at physiological concentrations SOCS2prevents STAT5 activation, thus inhibiting signaling, but at very high levels it canpreclude access of other important negative regulators to the GH receptor complex.STAT5 is known to play an essential role in immune cell development (109). IfSOCS2 is a key regulator of STAT5 activation by GH, an obvious corollary is thatSOCS2 may also regulate activation of STAT5 by other receptor systems, includingthose operating in lymphocytes. However, to date, no anomalies in lymphocytedevelopment or function have been reported in eitherSocs2−/− orSocs2transgenicmice.

SOCS and Innate Immunity

It is clear from the foregoing discussion that the study of SOCS proteins in immu-nity has primarily focused on the adaptive immune response, and clearly severalSOCS proteins have a central and indispensable role in the regulation of this armof host defense, primarily via attenuation of the actions of cytokines that influenceT cell development and function. The phagocytes of the innate immune systemare also regulated by several cytokines that are controlled by SOCS proteins, in-cluding, for example, IL-12 and the IFNs. It therefore follows that SOCS proteinsmake an important contribution to the regulation of the innate immune response.Indeed, macrophages lacking SOCS1 show enhanced killing of intracellularLeish-maniaparasites in cultures stimulated with LPS and IFNγ (74). The possibilitythat SOCS proteins are directly induced by microbial infection has been raised inrecent studies. Exposure to CpG-DNA triggers expression of SOCS1 and SOCS3in macrophages and dendritic cells via a pathway that does not require proteinsynthesis and appears independent of JAK-STAT signaling (114). Similarly, expo-sure of macrophages toLeishmania donovaniorListeria monocytogenesappears todirectly induce expression of SOCS3 (26, 115). These observations have provokedspeculation that SOCS expression may be induced directly via signals from theToll receptor family.

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LPS is a component of bacterial cell walls that binds the Toll receptor TLR4and induces expression of SOCS1 and SOCS3, although at least some componentof this activity may be indirect and due to LPS-induced autocrine factors suchas IFNs (28–31). Nevertheless,Socs1+/− or Socs1−/− mice showed dramaticallyincreased sensitivity to the lethal effects of LPS. Induction of nitric oxide syn-thesis and TNFα production were enhanced in SOCS1-deficient mice exposed toLPS, and LPS tolerance was significantly reduced (30, 31). Phosphorylation ofNF-κB and MAP kinase was increased in LPS-stimulatedSocs1−/−macrophagesrelative to wild-type control cells, and enforced SOCS1 expression blocked LPS-mediated activation of NF-κB. These data were interpreted to indicate that SOCS1is induced by LPS and feeds back to inhibit signals from TLR4 in a direct inhibitoryloop. However, until the specific proteins in the TLR signaling cascade that arethe targets of SOCS1 inhibition are identified, this model remains somewhat con-jectural. UnlikeSocs1−/− mice, mice in which theSocs3gene has been ablatedin macrophages show resistance to challenge with LPS. Enhanced inhibition ofmacrophage activation by IL-6 in macrophages lacking SOCS3 has been proposedto account for the reduced sensitivity in these mice (101), but the precise role ofSOCS proteins in LPS responses clearly remains enigmatic.

The prospect that SOCS proteins control signaling from chemokine receptorshas also emerged in recent studies. Upon ligand binding, chemokine receptors asso-ciate with guanine nucleotide-binding proteins (G proteins) resulting in activationof signaling pathways commonly associated with regulation of the cytoskeleton.However, it is clear that at least some chemokine receptors also activate JAK kinasesand recruit and activate members of the STAT family (116, 117). In a human B cellline, stimulation with CXCL12, which acts through the CXCR4 receptor, inducedexpression of SOCS3 via a JAK kinase-dependent and G protein–independentmechanism (118). Overexpression of SOCS1 or SOCS3, but not SOCS2, inhib-ited migration of fibroblasts in response to a gradient of CXCL12, but had noeffect on migration stimulated by CCL20 binding to CCR6. Biochemical studiesindicated that SOCS1 and SOCS3 could associate with the CXCR4 receptor andthe complex appeared to be stabilized by CXCL12 ligand binding (118).

Thus, in addition to the well-established role of SOCS proteins as classicalnegative feedback inhibitors of signaling from the hemopoietin class cytokinereceptors, the SOCS may also be part of feedback regulation of distinct receptorclasses including the Toll and chemokine receptors. Given the central role thatthese receptor systems play in modulating innate immune responses, dissection ofthe specific roles of SOCS proteins in innate immunity and diseases where theseresponses are disrupted is an important endeavor.

SOCS PROTEINS IN DISEASE

Cytokines play a pivotal role in the development and pathology of human disease,including diseases of the immune system. As it is now clear that SOCS proteinshave profound physiological actions, it seems inevitable that disruption of normal

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SOCS function will contribute to disease onset and progression. Moreover, thepotent inhibitory actions of SOCS proteins on cytokine signaling raise the excit-ing possibility that the SOCS proteins may prove to be excellent targets for thediscovery of drugs that can manipulate cytokine outcomes to resolve disease.

SOCS Proteins in Malignancy

It is well documented that a number of hematological malignancies are charac-terized by constitutive activation of the JAK-STAT pathway (119). A well-studiedexample is the chromosomal translocation t (9, 12) (p24;p13), which fuses theTELgene to the sequence encoding the kinase domain of JAK2, resulting in expres-sion of a fusion protein with deregulated kinase activity. This translocation hasbeen described in a portion of patients with T cell acute lymphoblastic leukemia(ALL), pre-B ALL, and atypical chronic myelogenous leukemia (120, 121). Re-cent data suggest that SOCS1 can inhibit transformation of cell lines expressingthe TEL-JAK fusion protein. SOCS1 inhibited kinase activity and autophosphory-lation of TEL-JAK2, but the inhibitory effect of SOCS1 was also dependent on theSOCS box domain, and it was demonstrated that expression of SOCS1 inducedproteasomal degradation of the oncogenic fusion protein (62, 122). Significantly,coexpression of SOCS1 with TEL-JAK2 in primary murine hematopoietic progen-itor cells prolonged the latency of leukemia in a transplantation model of leukemia(122). Ectopic expression of SOCS1 has also been shown to suppress prolifera-tion induced by activated forms of the c-Kit receptor and v-Abl protein as wellas suppressing metastasis of cells transformed by the Bcr-abl fusion oncoprotein(123).Socs1−/− fibroblasts were also found to be more sensitive than wild-typecontrols to transformation mediated by these tyrosine kinase oncogenes, as wellas exhibiting enhanced spontaneous transformation (123).

In a similar context, levels of SOCS2 expression appear significantly higherin cells from patients in CML blast crisis relative to that observed in the chronicphase of the disease, and the level of SOCS2 was downmodulated upon exposureof cells to drugs that inhibit the Bcr-abl oncoprotein (124). Overexpression ofSOCS2 in cells expressing Bcr-abl led to diminution of the transformed phenotype,suggesting that disruption of a negative regulatory loop involving SOCS2 maycontribute to CML. These studies raise the exciting possibility that SOCS proteinsmay prove useful in treatment of malignancies in which activation of specifictyrosine kinase oncoproteins plays a central role.

The role of SOCS1 as a potential tumor suppressor has also been raised in anal-yses of hepatocellular carcinoma. Aberrant DNA methylation at theSOCS1locusresulting in transcriptional silencing has been observed in a large portion of humanprimary hepatocellular carcinomas and hepatoblastomas (125–128). Restorationof SOCS1 expression in cells in which theSOCS1gene was silenced led to areduction in the transformed phenotype (125). Methylation and silencing at theSOCS1locus has now also been associated with significant numbers of patientswith multiple myeloma or acute myeloid leukemia (129, 130).

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Conversely, in cell lines generated from cutaneous T cell lymphoma and inchronic myeloid leukemia, constitutive SOCS3 expression has been documented(20, 131). Although the basis for this apparent deregulation of SOCS3 expressionand any role it may play in disease etiology remain unresolved, in both cases itwas observed that excessive SOCS3 expression correlated with resistance to IFNα.Because insensitivity to IFN has been observed in subsets of patients with severalleukemias, as well as in the treatment of hepatitis, these early studies raise thepossibility that specific patterns ofSOCSgene expression in individual patientsor tumors may influence the impact of IFN therapy and that therapeutic strategiesdesigned to inhibit SOCS action may prove beneficial in this context.

SOCS Proteins in Inflammatory Disease

Activation of STAT3 is a hallmark of animal models of colitis as well as humanCrohn’s disease and ulcerative colitis, and concomitant constitutive expressionof SOCS3 has been documented in these inflammatory diseases (132, 133). In amurine model of induced colitis in mice, transgenic mice expressing a dominant-negative mutant form of SOCS1 exhibited increased expression of STAT3 andsuffered a more severe colitis than wild-type control mice (132). Because themutant form of SOCS1 expressed in these mice interferes both with endogenousSOCS1 and SOCS3 activity, these data are consistent with the potential role forSOCS3 in regulating cytokines that contribute to inflammation in the bowel.

Similarly, activation of STAT3 and deregulated SOCS3 expression have alsobeen observed in the joint tissue of patients with rheumatoid arthritis (134). Inmurine models of antigen- or collagen-induced arthritis, periarticular administra-tion of an adenovirus producing SOCS3 led to reduced inflammation and jointswelling and significantly reduced cartilage and bone destruction (134). As in thecolitis models, it is proposed that the inflammatory cytokines that drive pathol-ogy act through STAT3 activation, and SOCS3 is induced in an attempt to controlthese signaling cascades. Because increasing local SOCS3 concentrations via genetherapy appeared to tip the balance between disease progression and suppression,therapeutic strategies that target SOCS3 expression or activity in patients withinflammatory diseases may prove effective.

Although most attention has focused on SOCS3 in inflammatory disease, recentstudies have also demonstrated that mice lacking SOCS1 display increased syn-ovial inflammation and joint destruction in an IL-1-driven model of experimentalarthritis that is dependent on a number of cytokines including GM-CSF, TNF-α,and IL-6 (135). In these animals, SOCS1 appeared to act in synovial macrophagesand fibroblasts to limit inflammation and joint destruction, as well as regulating Tcell proliferation (135).

The observation that SOCS3 appears to be selectively expressed in Th2 cellshas led to an examination of the role of SOCS3 in allergies such as atopic asthma,which is characterized by extensive infiltration of the airways by T cells express-ing Th2 cytokines. A positive correlation was evident between SOCS3 expression

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and asthma pathology, as well as serum IgE levels in patients with allergy (136).Socs3+/−mice or transgenic mice expressing a dominant-negative form of SOCS3exhibited decreased Th2 development. Conversely, transgenic mice constitutivelyexpressing the wild-type SOCS3 protein in splenic T cells showed increased Th2responses and in a mouse airway hypersensitivity model of asthma exhibited en-hanced pathological features (136). These observations support a role for SOCS3as a regulator of Th2 development and suggest that modulation of SOCS3 may rep-resent a worthwhile therapeutic strategy in immunological diseases characterizedby a Th1/Th2 imbalance.

SOCS proteins have also been implicated in inflammatory diseases of the skin.For example, biopsies taken from patients with psoriasis or allergic contact der-matitis exhibited high levels of SOCS1, SOCS2, and SOCS3 expression, whereasthese proteins were not detected in healthy skin (137). Together, these observationsprovide a promising basis for pursuing the contribution of SOCS proteins to inflam-matory and other immune disorders. However, in complex inflammatory diseasesthe contribution to pathology and host responses by a range of cytokines is likelyto be reflected by the induction and action of multiple SOCS proteins. Dissect-ing the crucial regulators of disease outcome from those SOCS proteins simplyexpressed as a secondary consequence of disease is an important experimentalchallenge.

CONCLUSION

Cytokines are crucial to maintaining health and play an important role in the onsetand progression of disease. Since the discovery of the SOCS proteins, researchershave recognized that negative feedback regulation of signal transduction also playsa central role in balancing the positive and deleterious consequences of cytokineaction. Despite the progress that has been made in understanding how cytokinesignalling is controlled, many challenges remain. For example, how does exposureto one cytokine modify a cell’s response to a subsequent stimuli? Do SOCS proteinsact in concert to regulate signalling? Can modulation of SOCS protein productionor activity lead to beneficial clinical outcomes? Addressing these questions islikely to require the coordinated efforts of chemists, biochemists, cell biologists,physiologists, and clinicians for many years to come.

TheAnnual Review of Immunologyis online at http://immunol.annualreviews.org

LITERATURE CITED

1. Nicola NA. 1994. An introduction to thecytokines. InGuidebook to Cytokines andTheir Receptors, ed. NA Nicola. NewYork: Oxford Univ. Press

2. Hilton DJ. 1994. An introduction to cy-tokine receptors. InGuidebook to Cy-tokines and Their Receptors, ed. NANicola. New York: Oxford Univ. Press

Ann

u. R

ev. I

mm

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. 200

4.22

:503

-529

. Dow

nloa

ded

from

ww

w.a

nnua

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s.or

gby

Bro

wn

Uni

vers

ity o

n 05

/08/

12. F

or p

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3. Gadina M, Hilton D, Johnston JA,Morinobu A, Lighvani A, et al. 2001. Sig-naling by type I and II cytokine recep-tors: ten years after.Curr. Opin. Immunol.13:363–73

4. Bazan JF. 1990. Haemopoietic receptorsand helical cytokines.Immunol. Today.11:350–54

5. Ihle JN, Kerr IM. 1995. Jaks and Stats insignalling by the cytokine receptor super-family. Trends Genet.11:69–74

6. Darnell JE Jr, Kerr IM, Stark GR. 1994.Jak-STAT pathways and transcriptionalactivation in response to IFNs and otherextracellular signaling proteins.Science264:1415–21

7. Darnell JE Jr. 1997. STATs and gene reg-ulation.Science277:1630–35

8. Yoshimura A, Ohkubo T, Kiguchi T,Jenkins NA, Gilbert DJ, et al. 1995. Anovel cytokine-inducible gene CIS en-codes an SH2-containing protein thatbinds to tyrosine-phosphorylated inter-leukin 3 and erythropoietin receptors.EMBO J.14:2816–26

9. Starr R, Willson TA, Viney EM, Mur-ray LJ, Rayner JR, et al. 1997. A fam-ily of cytokine-inducible inhibitors ofsignalling.Nature387:917–21

10. Endo TA, Masuhara M, Yokouchi M,Suzuki R, Sakamoto H, et al. 1997. A newprotein containing an SH2 domain that in-hibits JAK kinases.Nature387:921–24

11. Naka T, Narazaki M, Hirata M, Mat-sumoto T, Minamoto S, et al. 1997. Struc-ture and function of a new STAT-inducedSTAT inhibitor.Nature387:924–29

12. Minamoto S, Ikegame K, Ueno K,Narazaki M, Naka T, et al. 1997. Cloningand functional analysis of new membersof STAT induced STAT inhibitor (SSI)family: SSI-2 and SSI-3.Biochem. Bio-phys. Res. Commun.237:79–83

13. Hilton DJ, Richardson RT, AlexanderWS, Viney EM, Willson TA, et al. 1998.Twenty proteins containing a C-terminalSOCS box form five structural classes.Proc. Natl. Acad. Sci. USA95:114–19

14. Kile BT, Schulman BA, Alexander WS,Nicola NA, Martin HM, Hilton DJ. 2002.The SOCS box: a tale of destructionand degradation.Trends Biochem. Sci.27:235–41

15. Jegalian AG, Wu H. 2002. Regula-tion of Socs gene expression by theproto-oncoprotein GFI-1B: two routes forSTAT5 target gene induction by erythro-poietin.J. Biol. Chem.277:2345–52

16. Gregorieff A, Pyronnet S, Sonenberg N,Veillette A. 2000. Regulation of SOCS-1expression by translational repression.J.Biol. Chem.275:21596–604

17. Schluter G, Boinska D, Nieman-SeydeSC. 2000. Evidence for translational re-pression of the SOCS-1 major open read-ing frame by an upstream open readingframe.Biochem. Biophys. Res. Commun.268:255–61

18. He B, You L, Uematsu K, Matsangou M,Xu Z, et al. 2003. Cloning and charac-terization of a functional promoter of thehuman SOCS-3 gene.Biochem. Biophys.Res. Commun.301:386–91

19. Donnelly RP, Dickensheets H, FinbloomDS. 1999. The interleukin-10 signal trans-duction pathway and regulation of geneexpression in mononuclear phagocytes.J.Interferon Cytokine Res.19:563–73

20. Brender C, Nielsen M, Kaltoft K,Mikkelsen G, Zhang Q, et al. 2001.STAT3-mediated constitutive expressionof SOCS-3 in cutaneous T-cell lymphoma.Blood97:1056–62

21. Matsumoto A, Masuhara M, Mitsui K,Yokouchi M, Ohtsubo M, et al. 1997. CIS,a cytokine inducible SH2 protein, is a tar-get of the JAK-STAT5 pathway and mod-ulates STAT5 activation.Blood89:3148–54

22. Verdier F, Rabionet R, Gouilleux F,Beisenherz-Huss C, Varlet P, et al. 1998.A sequence of the CIS gene promoterinteracts preferentially with two associ-ated STAT5A dimers: a distinct biochem-ical difference between STAT5A andSTAT5B.Mol. Cell Biol.18:5852–60

Ann

u. R

ev. I

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. 200

4.22

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. Dow

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from

ww

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s.or

gby

Bro

wn

Uni

vers

ity o

n 05

/08/

12. F

or p

erso

nal u

se o

nly.



23. Davey HW, McLachlan MJ, Wilkins RJ,Hilton DJ, Adams TE. 1999. STAT5bmediates the GH-induced expression ofSOCS-2 and SOCS-3 mRNA in the liver.Mol. Cell Endocrinol.158:111–16

24. Feldman GM, Rosenthal LA, Liu X,Hayes MP, Wynshaw-Boris A, et al. 1997.STAT5A-deficient mice demonstrate a de-fect in granulocyte-macrophage colony-stimulating factor-induced proliferationand gene expression.Blood90:1768–76

25. Lee CK, Raz R, Gimeno R, Gertner R,Wistinghausen B, et al. 2002. STAT3 is anegative regulator of granulopoiesis but isnot required for G-CSF-dependent differ-entiation.Immunity17:63–72

26. Stoiber D, Stockinger S, Steinlein P, Ko-varik J, Decker T. 2001. Listeria monocy-togenes modulates macrophage cytokineresponses through STAT serine phospho-rylation and the induction of suppres-sor of cytokine signaling 3.J. Immunol.166:466–72

27. Gautron L, Lafon P, Tramu G, LayeS. 2003. In vivo activation of theinterleukin-6 receptor/gp130 signalingpathway in pituitary corticotropes oflipopolysaccharide-treated rats.Neuroen-docrinology77:32–43

28. Crespo A, Filla MB, Russell SW, Mur-phy WJ. 2000. Indirect induction ofsuppressor of cytokine signalling-1 inmacrophages stimulated with bacteriallipopolysaccharide: partial role of au-tocrine/paracrine interferon-alpha/beta.Biochem. J.349:99–104

29. Stoiber D, Kovarik P, Cohney S,Johnston JA, Steinlein P, Decker T.1999. Lipopolysaccharide induces inmacrophages the synthesis of the suppres-sor of cytokine signaling 3 and suppressessignal transduction in response to the ac-tivating factor IFN-gamma.J. Immunol.163:2640–47

30. Nakagawa R, Naka T, Tsutsui H, FujimotoM, Kimura A, et al. 2002. SOCS-1 partic-ipates in negative regulation of LPS re-sponses.Immunity17:677–87

31. Kinjyo I, Hanada T, Inagaki-Ohara K,Mori H, Aki D, et al. 2002. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation.Immunity17:583–91

32. Yasukawa H, Misawa H, Sakamoto H,Masuhara M, Sasaki A, et al. 1999. TheJAK-binding protein JAB inhibits Janustyrosine kinase activity through bindingin the activation loop.EMBO J.18:1309–20

33. Sporri B, Kovanen PE, Sasaki A,Yoshimura A, Leonard WJ. 2001.JAB/SOCS1/SSI-1 is an interleukin-2-induced inhibitor of IL-2 signaling.Blood97:221–26

34. Nicholson SE, Willson TA, Farley A, StarrR, Zhang JG, et al. 1999. Mutational anal-yses of the SOCS proteins suggest a dualdomain requirement but distinct mecha-nisms for inhibition of LIF and IL-6 signaltransduction.EMBO J.18:375–85

35. Fairlie WD, De Souza D, Nicola NA, BacaM. 2003. Negative regulation of gp130signalling mediated through tyrosine-757is not dependent on the recruitment ofSHP2.Biochem. J.372:495–502

36. De Souza D, Fabri LJ, Nash A, Hilton DJ,Nicola NA, Baca M. 2002. SH2 domainsfrom suppressor of cytokine signaling-3and protein tyrosine phosphatase SHP-2have similar binding specificities.Bio-chemistry41:9229–36

37. Nicholson SE, De Souza D, Fabri LJ,Corbin J, Willson TA, et al. 2000. Sup-pressor of cytokine signaling-3 prefer-entially binds to the SHP-2-binding siteon the shared cytokine receptor sub-unit gp130.Proc. Natl. Acad. Sci. USA97:6493–98

38. Schmitz J, Weissenbach M, Haan S, Hein-rich PC, Schaper F. 2000. SOCS3 ex-erts its inhibitory function on interleukin-6 signal transduction through the SHP2recruitment site of gp130.J. Biol. Chem.275:12848–56

39. Lehmann U, Schmitz J, Weissenbach M,Sobota RM, Hortner M, et al. 2003.

Ann

u. R

ev. I

mm

unol

. 200

4.22

:503

-529

. Dow

nloa

ded

from

ww

w.a

nnua

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s.or

gby

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wn

Uni

vers

ity o

n 05

/08/

12. F

or p

erso

nal u

se o

nly.



SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6signaling through gp130.J. Biol. Chem.278:661–71

40. Friederichs K, Schmitz J, WeissenbachM, Heinrich PC, Schaper F. 2001.Interleukin-6-induced proliferation ofpre-B cells mediated by receptor com-plexes lacking the SHP2/SOCS3 recruit-ment sites revisited.Eur. J. Biochem.268:6401–7

41. Bjorbak C, Lavery HJ, Bates SH, Ol-son RK, Davis SM, et al. 2000. SOCS3mediates feedback inhibition of the lep-tin receptor via Tyr985.J. Biol. Chem.275:40649–57

42. Eyckerman S, Broekaert D, Verhee A,Vandekerckhove J, Tavernier J. 2000.Identification of the Y985 and Y1077motifs as SOCS3 recruitment sites inthe murine leptin receptor.FEBS Lett.486:33–37

43. Hermans MH, van de Geijn GJ, Antonis-sen C, Gits J, van Leeuwen D, et al.2003. Signaling mechanisms coupledto tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid pro-genitor cells.Blood101:2584–90

44. Hortner M, Nielsch U, Mayr LM, John-ston JA, Heinrich PC, Haan S. 2002.Suppressor of cytokine signaling-3 isrecruited to the activated granulocyte-colony stimulating factor receptor andmodulates its signal transduction.J. Im-munol.169:1219–27

45. Hansen JA, Lindberg K, Hilton DJ,Nielsen JH, Billestrup N. 1999. Mechan-ism of inhibition of growth hormone re-ceptor signaling by suppressor of cyto-kine signaling proteins.Mol. Endocrinol.13:1832–43

46. Ram PA, Waxman DJ. 1999. SOCS/CISprotein inhibition of growth hormone-stimulated STAT5 signaling by multiplemechanisms.J. Biol. Chem.274:35553–61

47. Hortner M, Nielsch U, Mayr LM, Hein-

rich PC, Haan S. 2002. A new high affin-ity binding site for suppressor of cytokinesignaling-3 on the erythropoietin receptor.Eur. J. Biochem.269:2516–26

48. Sasaki A, Yasukawa H, Shouda T, Ki-tamura T, Dikic I, Yoshimura A. 2000.CIS3/SOCS-3 suppresses erythropoietin(EPO) signaling by binding the EPO re-ceptor and JAK2.J. Biol. Chem.275:29338–47

49. Cohney SJ, Sanden D, Cacalano NA,Yoshimura A, Mui A, et al. 1999. SOCS-3is tyrosine phosphorylated in response tointerleukin-2 and suppresses STAT5 phos-phorylation and lymphocyte proliferation.Mol. Cell Biol.19:4980–88

50. Lejeune D, Demoulin JB, Renauld JC.2001. Interleukin 9 induces expression ofthree cytokine signal inhibitors: cytokine-inducible SH2-containing protein, sup-pressor of cytokine signalling (SOCS)-2and SOCS-3, but only SOCS-3 over-expression suppresses interleukin 9 sig-nalling.Biochem. J.353:109–16

51. Losman J, Chen XP, Jiang H, Pan PY,Kashiwada M, et al. 1999. IL-4 signal-ing is regulated through the recruitmentof phosphatases, kinases, and SOCS pro-teins to the receptor complex.Cold SpringHarbor Symp. Quant. Biol.64:405–16

52. Eyckerman S, Verhee A, der HeydenJV, Lemmens I, Ostade XV, et al. 2001.Design and application of a cytokine-receptor-based interaction trap.Nat. CellBiol. 3:1114–19

53. Dif F, Saunier E, Demeneix B, KellyPA, Edery M. 2001. Cytokine-inducibleSH2-containing protein suppresses PRLsignaling by binding the PRL receptor.Endocrinology142:5286–93

54. Aman MJ, Migone T-S, Sasaki A, As-cherman DP, Zhu M, et al. 1999. CISassociates with the interleukin-2 recep-tor β chain and inhibits interleukin-2-dependent signaling.J. Biol. Chem.274:30266–72

55. Pezet A, Favre H, Kelly PA, EderyM. 1999. Inhibition and restoration of

Ann

u. R

ev. I

mm

unol

. 200

4.22

:503

-529

. Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Bro

wn

Uni

vers

ity o

n 05

/08/

12. F

or p

erso

nal u

se o

nly.



prolactin signal transduction by suppres-sors of cytokine signaling.J. Biol. Chem.274:24497–502

56. Greenhalgh CJ, Metcalf D, Thaus AL,Corbin JE, Uren R, et al. 2002. Bio-logical evidence that SOCS-2 can acteither as an enhancer or suppressor ofgrowth hormone signaling.J. Biol. Chem.277:40181–14

57. Narazaki M, Fujimoto M, Matsumoto T,Morita Y, Saito H, et al. 1998. Three dis-tinct domains of SSI-1/SOCS-1/JAB pro-tein are required for its suppression of in-terleukin 6 signaling.Proc. Natl. Acad.Sci. USA95:13130–34

58. Zhang JG, Farley A, Nicholson SE, Will-son TA, Zugaro LM, et al. 1999. The con-served SOCS box motif in suppressors ofcytokine signaling binds to elongins B andC and may couple bound proteins to pro-teasomal degradation.Proc. Natl. Acad.Sci. USA96:2071–76

59. Kamura T, Sato S, Haque D, Liu L, KaelinWG, et al. 1998. The elongin BC complexinteracts with the conserved SOCS-boxmotif present in members of the SOCS,ras, WD-40 repeat, and ankyrin repeatfamilies.Genes Dev.12:3872–81

60. Ungureanu D, Saharinen P, Junttila I,Hilton DJ, Silvennoinen O. 2002. Reg-ulation of Jak2 through the ubiquitin-proteasome pathway involves phosphory-lation of Jak2 on Y1007 and interactionwith SOCS-1.Mol. Cell Biol. 22:3316–26

61. Monni R, Santos SC, Mauchauffe M,Berger R, Ghysdael J, et al. 2001. TheTEL-Jak2 oncoprotein induces Socs1 ex-pression and altered cytokine response inBa/F3 cells.Oncogene20:849–58

62. Kamizono S, Hanada T, Yasukawa H,Minoguchi S, Kato R, et al. 2001.The SOCS box of SOCS-1 acceleratesubiquitin-dependent proteolysis of TEL-JAK2. J. Biol. Chem.276:12530–38

63. Zhang JG, Metcalf D, Rakar S, AsimakisM, Greenhalgh CJ, et al. 2001. The SOCSbox of suppressor of cytokine signaling-1

is important for inhibition of cytokine ac-tion in vivo. Proc. Natl. Acad. Sci. USA98:13261–65

64. Alexander WS. 2002. Suppressors of cy-tokine signalling (SOCS) in the immunesystem.Nat. Rev. Immunol.2:410–16

65. Krebs DL, Hilton DJ. 2001. SOCS pro-teins: negative regulators of cytokine sig-naling.Stem Cells19:378–87

66. Yoshimura A. 1998. The CIS/JAB family:novel negative regulators of JAK signal-ing pathways.Leukemia12:1851–57

67. Naka T, Matsumoto T, Narazaki M,Fujimoto M, Morita Y, et al. 1998. Accel-erated apoptosis of lymphocytes by aug-mented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice.Proc. Natl. Acad. Sci. USA95:15577–82

68. Starr R, Metcalf D, Elefanty AG, BryshaM, Willson TA, et al. 1998. Liver degen-eration and lymphoid deficiencies in micelacking suppressor of cytokine signaling-1. Proc. Natl. Acad. Sci. USA95:14395–99

69. Kawazoe Y, Naka T, Fujimoto M, Koh-zaki H, Morita Y, et al. 2001. Signaltransducer and activator of transcription(STAT)-induced STAT inhibitor 1 (SSI-1)/suppressor of cytokine signaling 1(SOCS1) inhibits insulin signal transduc-tion pathway through modulating insulinreceptor substrate 1 (IRS-1) phosphoryla-tion. J. Exp. Med.193:263–69

70. Lindeman GJ, Wittlin S, Lada H, NaylorMJ, Santamaria M, et al. 2001. SOCS1deficiency results in accelerated mam-mary gland development and rescues lac-tation in prolactin receptor-deficient mice.Genes Dev.15:1631–36

71. Cornish AL, Davey GM, Metcalf D, Pur-ton JF, Corbin JE, et al. 2003. Suppressorof cytokine signaling-1 has IFN-gamma-independent actions in T cell homeostasis.J. Immunol.170:878–86

72. Marine JC, Topham DJ, McKay C, WangD, Parganas E, et al. 1999. SOCS1 de-ficiency causes a lymphocyte-dependentperinatal lethality.Cell 98:609–16

Ann

u. R

ev. I

mm

unol

. 200

4.22

:503

-529

. Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Bro

wn

Uni

vers

ity o

n 05

/08/

12. F

or p

erso

nal u

se o

nly.



73. Gresser I, Tovey MG, Maury C,Chouroulinkov I. 1975. Lethality ofinterferon preparations for newbornmice.Nature258:76–78

74. Alexander WS, Starr R, Fenner JE, ScottCL, Handman E, et al. 1999. SOCS1 isa critical inhibitor of interferon gammasignaling and prevents the potentially fa-tal neonatal actions of this cytokine.Cell98:597–608

75. Metcalf D, Di Rago L, Mifsud S, Hart-ley L, Alexander WS. 2000. The develop-ment of fatal myocarditis and polymyosi-tis in mice heterozygous for IFN-gammaand lacking the SOCS-1 gene.Proc. Natl.Acad. Sci. USA97:9174–79

76. Metcalf D, Alexander WS, Elefanty AG,Nicola NA, Hilton DJ, et al. 1999. Aber-rant hematopoiesis in mice with inac-tivation of the gene encoding SOCS-1.Leukemia13:926–34

77. Brysha M, Zhang JG, Bertolino P, CorbinJE, Alexander WS, et al. 2001. Suppres-sor of cytokine signaling-1 attenuates theduration of interferon gamma signal trans-duction in vitro and in vivo.J. Biol. Chem.276:22086–89

78. Grawunder U, Melchers F, Rolink A.1993. Interferon-gamma arrests prolif-eration and causes apoptosis in stro-mal cell/interleukin-7-dependent normalmurine pre-B cell lines and clonesin vitro, but does not induce differ-entiation to surface immunoglobulin-positive B cells.Eur. J. Immunol.23:544–51

79. Matsuda T, Yamamoto T, Kishi H,Yoshimura A, Muraguchi A. 2000. SOCS-1 can suppress CD3zeta- and Syk-mediated NF-AT activation in a non-lymphoid cell line.FEBS Lett.472:235–40

80. Naka T, Tsutsui H, Fujimoto M, KawazoeY, Kohzaki H, et al. 2001. SOCS-1/SSI-1-deficient NKT cells participate in severehepatitis through dysregulated cross-talkinhibition of IFN-gamma and IL-4 signal-ing in vivo. Immunity14:535–45

81. Eyles JL, Metcalf D, Grusby MJ, HiltonDJ, Starr R. 2002. Negative regulationof interleukin-12 signaling by suppressorof cytokine signaling-1.J. Biol. Chem.277:43735–40

82. Chong MM, Thomas HE, Kay TW. 2002.Suppressor of cytokine signaling-1 regu-lates the sensitivity of pancreatic beta cellsto tumor necrosis factor.J. Biol. Chem.277:27945–52

83. Morita Y, Naka T, Kawazoe Y, Fuji-moto M, Narazaki M, et al. 2000. Signalstransducers and activators of transcrip-tion (STAT)-induced STAT inhibitor-1(SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosisfactor alpha-induced cell death in fibrob-lasts.Proc. Natl. Acad. Sci. USA97:5405–10

84. Chong MM, Cornish AL, Darwiche R,Stanley EG, Purton JF, et al. 2003. Sup-pressor of cytokine signaling-1 is a crit-ical regulator of interleukin-7-dependentCD8+ T cell differentiation. Immunity18:475–87

85. Metcalf D, Mifsud S, Di Rago L, Alexan-der WS. 2003. The lethal effects of trans-plantation of Socs1−/− bone marrow cellsinto irradiated adult syngeneic recipients.Proc. Natl. Acad. Sci. USA100:8436–41

86. Trop S, De Sepulveda P, Zuniga-PfluckerJC, Rottapel R. 2001. Overexpression ofsuppressor of cytokine signaling-1 im-pairs pre-T-cell receptor-induced prolifer-ation but not differentiation of immaturethymocytes.Blood97:2269–77

87. Fujimoto M, Naka T, Nakagawa R, Kawa-zoe Y, Morita Y, et al. 2000. Defectivethymocyte development and perturbedhomeostasis of T cells in STAT-inducedSTAT inhibitor-1/suppressors of cytokinesignaling-1 transgenic mice.J. Immunol.165:1799–806

88. Jameson SC. 2002. Maintaining the norm:T-cell homeostasis.Nat. Rev. Immunol.2:547–56

89. Cornish AL, Chong MM, Davey GM,Darwiche R, Nicola NA, et al. 2003.

Ann

u. R

ev. I

mm

unol

. 200

4.22

:503

-529

. Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Bro

wn

Uni

vers

ity o

n 05

/08/

12. F

or p

erso

nal u

se o

nly.



SOCS-1 regulates signaling in responseto IL-2 and other gamma c-dependentcytokines in peripheral T cells.J. Biol.Chem.278:22755–61

90. Losman JA, Chen XP, Hilton D, RothmanP. 1999. Cutting edge: SOCS-1 is a po-tent inhibitor of IL-4 signal transduction.J. Immunol.162:3770–74

91. Metcalf D, Mifsud S, Di Rago L, NicolaNA, Hilton DJ, Alexander WS. 2002.Polycystic kidneys and chronic inflam-matory lesions are the delayed conse-quences of loss of the suppressor of cy-tokine signaling-1 (SOCS-1).Proc. Natl.Acad. Sci. USA99:943–48

92. Egwuagu CE, Yu CR, Zhang M, MahdiRM, Kim SJ, Gery I. 2002. Suppressors ofcytokine signaling proteins are differen-tially expressed in Th1 and Th2 cells: im-plications for Th cell lineage commitmentand maintenance.J. Immunol.168:3181–87

93. Fujimoto M, Tsutsui H, Yumikura-Futatsugi S, Ueda H, Xingshou O, et al.2002. A regulatory role for suppressor ofcytokine signaling-1 in T(h) polarizationin vivo. Int. Immunol.14:1343–50

94. Bullen DV, Baldwin TM, Curtis JM,Alexander WS, Handman E. 2003. Per-sistence of lesions in suppressor of cy-tokine signaling-1-deficient mice infectedwith Leishmania major.J. Immunol.170:4267–72

95. Diehl S, Anguita J, Hoffmeyer A, Zap-ton T, Ihle JN, et al. 2000. Inhibition ofTh1 differentiation by IL-6 is mediatedby SOCS1.Immunity13:805–15

96. Marine JC, McKay C, Wang D, TophamDJ, Parganas E, et al. 1999. SOCS3 is es-sential in the regulation of fetal liver ery-thropoiesis.Cell 98:617–27

97. Roberts AW, Robb L, Rakar S, HartleyL, Cluse L, et al. 2001. Placental defectsand embryonic lethality in mice lackingsuppressor of cytokine signaling 3.Proc.Natl. Acad. Sci. USA98:9324–29

98. Bischof P, Haenggeli L, Campana A.1995. Effect of leukemia inhibitory fac-

tor on human cytotrophoblast differenti-ation along the invasive pathway.Am. J.Reprod. Immunol.34:225–30

99. Takahashi Y, Carpino N, Cross JC, TorresM, Parganas E, Ihle JN. 2003. SOCS3: anessential regulator of LIF receptor signal-ing in trophoblast giant cell differentia-tion. EMBO J.22:372–84

100. Croker BA, Krebs DL, Zhang JG,Wormald S, Willson TA, et al. 2003.SOCS3 negatively regulates IL-6 signal-ing in vivo. Nat. Immunol.4:540–45

101. Yasukawa H, Ohishi M, Mori H, Mu-rakami M, Chinen T, et al. 2003. IL-6induces an anti-inflammatory response inthe absence of SOCS3 in macrophages.Nat. Immunol4:551–56

102. Lang R, Pauleau AL, Parganas E, Taka-hashi Y, Mages J, et al. 2003. SOCS3 reg-ulates the plasticity of gp130 signaling.Nat. Immunol.4:546–50

103. Song MM, Shuai K. 1998. The sup-pressor of cytokine signaling (SOCS) 1and SOCS3 but not SOCS2 proteins in-hibit interferon-mediated antiviral and an-tiproliferative activities.J. Biol. Chem.273:35056–62

104. Costa-Pereira AP, Tininini S, Strobl B,Alonzi T, Schlaak JF, et al. 2002. Mu-tational switch of an IL-6 response toan interferon-gamma-like response.Proc.Natl. Acad. Sci. USA99:8043–47

105. Yu CR, Mahdi RM, Ebong S, Vistica BP,Gery I, Egwuagu CE. 2003. Suppressor ofcytokine signaling 3 (SOCS3) regulatesproliferation and activation of T-helpercells.J. Biol. Chem.278:29752–59

106. Matsumoto A, Seki Y, Watanabe R,Hayashi K, Johnston JA, et al. 2003. Arole of suppressor of cytokine signaling3 (SOCS3/CIS3/SSI3) in CD28-mediatedinterleukin 2 production.J. Exp. Med.197:425–36

107. Seki Y, Hayashi K, Matsumoto A, SekiN, Tsukada J, et al. 2002. Expressionof the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2

Ann

u. R

ev. I

mm

unol

. 200

4.22

:503

-529

. Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Bro

wn

Uni

vers

ity o

n 05

/08/

12. F

or p

erso

nal u

se o

nly.



differentiation.Proc. Natl. Acad. Sci. USA99:13003–8

108. Teglund S, McKay C, Schuetz E, vanDeursen JM, Stravopodis D, et al. 1998.Stat5a and Stat5b proteins have essentialand nonessential, or redundant, roles incytokine responses.Cell 93:841–50

109. Matsumoto A, Seki Y, Kubo M, Oht-suka S, Suzuki A, et al. 1999. Sup-pression of STAT5 functions in liver,mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 trans-genic mice.Mol. Cell Biol.19:6396–407

110. Li S, Chen S, Xu X, Sundstedt A, PaulssonKM, et al. 2000. Cytokine-induced Src ho-mology 2 protein (CIS) promotes T cellreceptor-mediated proliferation and pro-longs survival of activated T cells.J. Exp.Med.191:985–94

111. Metcalf D, Greenhalgh CJ, Viney E, Will-son TA, Starr R, et al. 2000. Gigantismin mice lacking suppressor of cytokinesignalling-2.Nature405:1069–73

112. Greenhalgh CJ, Bertolino P, Asa SL, Met-calf D, Corbin JE, et al. 2002. Growthenhancement in suppressor of cytokinesignaling 2 (SOCS-2)-deficient mice isdependent on signal transducer and acti-vator of transcription 5b (STAT5b).Mol.Endocrinol.16:1394–406

113. Favre H, Benhamou A, Finidori J, KellyPA, Edery M. 1999. Dual effects of sup-pressor of cytokine signaling (SOCS-2)on growth hormone signal transduction.FEBS Lett.453:63–66

114. Dalpke AH, Opper S, Zimmermann S,Heeg K. 2001. Suppressors of cytokinesignaling (SOCS)-1 and SOCS-3 are in-duced by CpG-DNA and modulate cy-tokine responses in APCs.J. Immunol.166:7082–89

115. Bertholet S, Dickensheets HL, Sheikh F,Gam AA, Donnelly RP, Kenney RT. 2003.Leishmania donovani-induced expressionof suppressor of cytokine signaling 3 inhuman macrophages: a novel mechanismfor intracellular parasite suppression ofactivation.Infect. Immun.71:2095–101

116. Vila-Coro AJ, Rodriguez-Frade JM,Martin De Ana A, Moreno-Ortiz MC,Martinez AC, Mellado M. 1999. Thechemokine SDF-1alpha triggers CXCR4receptor dimerization and activates theJAK/STAT pathway.FASEB J.13:1699–710

117. Mellado M, Rodriguez-Frade JM, AragayA, del Real G, Martin AM, et al. 1998. Thechemokine monocyte chemotactic protein1 triggers Janus kinase 2 activation andtyrosine phosphorylation of the CCR2Breceptor.J. Immunol.161:805–13

118. Soriano SF, Hernanz-Falcon P, Rodri-guez-Frade JM, De Ana AM, Garzon R,et al. 2002. Functional inactivation ofCXC chemokine receptor 4-mediated re-sponses through SOCS3 up-regulation.J.Exp. Med.196:311–21

119. Ward AC, Touw I, Yoshimura A. 2000.The Jak-Stat pathway in normal andperturbed hematopoiesis.Blood 95:19–29

120. Lacronique V, Boureux A, Valle VD,Poirel H, Quang CT, et al. 1997. A TEL-JAK2 fusion protein with constitutive ki-nase activity in human leukemia.Science278:1309–12

121. Peeters P, Raynaud SD, Cools J, Wlo-darska I, Grosgeorge J, et al. 1997. Fusionof TEL, the ETS-variant gene 6 (ETV6),to the receptor-associated kinase JAK2as a result of t(9;12) in a lymphoid andt(9;15;12) in a myeloid leukemia.Blood90:2535–40

122. Frantsve J, Schwaller J, Sternberg DW,Kutok J, Gilliland DG. 2001. Socs-1inhibits TEL-JAK2-mediated transforma-tion of hematopoietic cells through inhi-bition of JAK2 kinase activity and induc-tion of proteasome-mediated degradation.Mol. Cell Biol.21:3547–57

123. Rottapel R, Ilangumaran S, Neale C, LaRose J, Ho JM, et al. 2002. The tumorsuppressor activity of SOCS-1.Oncogene21:4351–62

124. Schultheis B, Carapeti-Marootian M,Hochhaus A, Weisser A, Goldman JM,

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Melo JV. 2002. Overexpression of SOCS-2 in advanced stages of chronic myeloidleukemia: possible inadequacy of anegative feedback mechanism.Blood99:1766–75

125. Yoshikawa H, Matsubara K, Qian GS,Jackson P, Groopman JD, et al. 2001.SOCS-1, a negative regulator of theJAK/STAT pathway, is silenced by methy-lation in human hepatocellular carcinomaand shows growth-suppression activity.Nat. Genet.28:29–35

126. Nagai H, Kim YS, Konishi N, BabaM, Kubota T, et al. 2002. Combinedhypermethylation and chromosome lossassociated with inactivation of SSI-1/SOCS-1/JAB gene in human hepatocel-lular carcinomas.Cancer Lett.186:59–65

127. Nagai H, Naka T, Terada Y, Komazaki T,Yabe A, et al. 2003. Hypermethylation as-sociated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in humanhepatoblastomas.J. Hum. Genet.48:65–69

128. Nagai H, Kim YS, Lee KT, Chu MY,Konishi N, et al. 2001. Inactivation of SSI-1, a JAK/STAT inhibitor, in human hepa-tocellular carcinomas, as revealed by two-dimensional electrophoresis.J. Hepatol.34:416–21

129. Chen CY, Tsay W, Tang JL, Shen HL,Lin SW, et al. 2003. SOCS1 methylationin patients with newly diagnosed acutemyeloid leukemia.Genes ChromosomesCancer37:300–5

130. Galm O, Yoshikawa H, Esteller M, OsiekaR, Herman JG. 2003. SOCS-1, a nega-tive regulator of cytokine signaling, is fre-quently silenced by methylation in multi-ple myeloma.Blood101:2784–88

131. Sakai I, Takeuchi K, Yamauchi H, NarumiH, Fujita S. 2002. Constitutive expressionof SOCS3 confers resistance to IFN-alphain chronic myelogenous leukemia cells.Blood100:2926–31

132. Suzuki A, Hanada T, Mitsuyama K,Yoshida T, Kamizono S, et al. 2001.

CIS3/SOCS3/SSI3 plays a negative regu-latory role in STAT3 activation and intesti-nal inflammation.J. Exp. Med.193:471–81

133. Lovato P, Brender C, Agnholt J, Kelsen J,Kaltoft K, et al. 2003. Constitutive STAT3activation in intestinal T cells from pa-tients with Crohn’s disease.J. Biol. Chem.278:16777–81

134. Shouda T, Yoshida T, Hanada T, WakiokaT, Oishi M, et al. 2001. Induction of thecytokine signal regulator SOCS3/CIS3 asa therapeutic strategy for treating inflam-matory arthritis.J. Clin. Invest.108:1781–88

135. Egan PJ, Lawlor KE, Alexander WS,Wicks IP. 2003. Suppressor of cytokinesignaling-1 regulates acute inflammatoryarthritis and T cell activation.J. Clin. In-vest.111:915–24

136. Seki YI, Inoue H, Nagata N, Hayashi K,Fukuyama S, et al. 2003. SOCS-3 reg-ulates onset and maintenance of T(H)2-mediated allergic responses.Nat. Med.9:1047–54

137. Federici M, Giustizieri ML, Scarponi C,Girolomoni G, Albanesi C. 2002. Im-paired IFN-gamma-dependent inflamma-tory responses in human keratinocytesoverexpressing the suppressor of cytokinesignaling 1.J. Immunol.169:434–42

138. Krebs DL, Uren RT, Metcalf D, Rakar S,Zhang JG, et al. 2002. SOCS-6 binds to in-sulin receptor substrate 4, and mice lack-ing the SOCS-6 gene exhibit mild growthretardation. Mol. Cell Biol. 22:4567–78

139. Jones SA, Rose-John S. 2002. The roleof soluble receptors in cytokine biol-ogy: the agonistic properties of the sIL-6R/IL-6 complex.Biochim. Biophys. Acta1592:251–63

140. Jiao H, Berrada K, Yang W, Tabrizi M,Platanias LC, Yi T. 1996. Direct associa-tion with and dephosphorylation of Jak2kinase by the SH2-domain-containingprotein tyrosine phosphatase SHP-1.Mol.Cell. Biol.16:6985–92

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141. Ihle JN, Witthuhn BA, Quelle FW, Sil-vennoinen O, Tang B, Yi T. 1994.Protein tyrosine phosphorylation in theregulation of hematopoiesis by recep-tors of the cytokine-receptor superfamily.Blood Cells20:65–80, discussion 2

142. Qu CK. 2002. Role of the SHP-2 tyrosinephosphatase in cytokine-induced signal-ing and cellular response.Biochim. Bio-phys. Acta1592:297–301

143. Irie-Sasaki J, Sasaki T, Matsumoto W,Opavsky A, Cheng M, et al. 2001. CD45is a JAK phosphatase and negatively regu-lates cytokine receptor signalling.Nature409:349–54

144. Yamada T, Zhu D, Saxon A, ZhangK. 2002. CD45 controls interleukin-4-mediated IgE class switch recombination

in human B cells through its function as aJanus kinase phosphatase.J. Biol. Chem.277:28830–35

145. Yamamoto T, Sekine Y, Kashima K, Kub-ota A, Sato N, et al. 2002. The nuclearisoform of protein-tyrosine phosphataseTC-PTP regulates interleukin-6-mediatedsignaling pathway through STAT3 de-phosphorylation.Biochem. Biophys. Res.Commun.297:811–17

146. Aoki N, Matsuda T. 2002. A nuclear pro-tein tyrosine phosphatase TC-PTP is apotential negative regulator of the PRL-mediated signaling pathway: dephospho-rylation and deactivation of signal trans-ducer and activator of transcription 5aand 5b by TC-PTP in nucleus.Mol. En-docrinol.16:58–69

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SOCS PROTEINS AND THE IMMUNE RESPONSE C-1

Fig

ure

1C

ytok

ine

sign

al tr

ansd

uctio

n is

reg

ulat

ed a

t man

y le

vels

. Cyt

okin

es a

ct b

y bi

ndin

g to

mem

bers

of

the

hem

opoi

etin

rec

epto

r fa

m-

ily a

nd i

nduc

ing

thei

r di

mer

izat

ion,

res

ultin

g in

cro

ss-p

hosp

hory

latio

n of

non

cova

lent

ly a

ssoc

iate

d ja

nus

kina

ses

(JA

Ks)

. JA

Ks

phos

pho-

ryla

te t

yros

ine

resi

dues

in

the

rece

ptor

cyt

opla

smic

dom

ain,

cre

atin

g do

ckin

g si

tes

for

prot

eins

suc

h as

the

sig

nal

tran

sduc

ers

and

activ

a-to

rs o

f tr

ansc

ript

ion

(STA

Ts).

Dim

eric

STA

Ts m

igra

te to

the

nucl

eus

whe

re th

ey in

crea

se tr

ansc

ript

ion

of g

enes

impo

rtan

t for

elic

iting

the

biol

ogic

al e

ffec

t of

the

cyto

kine

. Sig

nalin

g is

con

trol

led

at m

any

leve

ls o

utsi

de th

e ce

ll an

d w

ithin

the

cell.

Sec

rete

d an

d m

embr

ane

asso

-ci

ated

rec

epto

rs c

an a

ct a

s an

tago

nist

s by

bin

ding

fre

e cy

toki

ne (

139)

. Act

ivat

ed r

ecep

tors

with

bou

nd c

ytok

ine

are

inte

rnal

ized

and

deg

ra-

ded,

whe

reas

act

ivat

ed s

igna

ling

com

pone

nts

can

be d

epho

spho

ryla

ted

by a

ple

thor

a of

pho

spha

tase

s in

clud

ing

the

SH2

dom

ain

cont

ain-

ing

phos

phat

ases

SH

P1 (

140,

141

) an

d SH

P2 (

142)

, the

tran

smem

bran

e ph

osph

atas

e C

D45

(14

3, 1

44)

and

STA

Tph

osph

atas

es (

145,

146

).

HI-RES-IY22-17-Alexander 3/12/2004 2:09 PM Page 1

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C-2 ALEXANDER ■ HILTON

Figure 2 Structure of SOCS proteins. All eight members of the SOCS protein family con-tain an N-terminal region of varying length and sequence, a central SH2 domain, and a C-terminal SOCS box. SOCS proteins are known by a range of aliases: SOCS1 = SSI1 =JAB, SOCS2 = SSI2 = CIS2, SOCS3 = SSI3 = CIS3, SOCS4 = CIS7, SOCS5 = CIS6,SOCS6 = CIS4, SOCS7 = CIS5 = NAP4.


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SOCS PROTEINS AND THE IMMUNE RESPONSE C-3

Fig

ure

3SO

CS

prot

eins

act

in

a ne

gativ

e fe

edba

ck l

oop

to a

ttenu

ate

sign

alin

g. U

pon

bind

ing

to t

heir

rec

epto

r, cy

toki

nes

activ

ate

the

JAK

/STA

Tpa

thw

ay, r

esul

ting

in a

n in

crea

se i

n th

e tr

ansc

ript

ion

of n

ot o

nly

the

gene

s m

edia

ting

the

biol

ogic

al e

ffec

t of

the

cyt

okin

e, b

utal

so th

e SO

CS

gene

s. O

nce

prod

uced

, SO

CS

prot

eins

can

inhi

bit s

igna

ling

by b

indi

ng to

pho

spho

ryla

ted

JAK

s an

d re

cept

ors

and

can

inte

r-ac

t with

com

pone

nts

of E

3 ub

iqui

tin li

gase

s to

pol

yubi

quity

late

JA

Ks

and

targ

et th

em f

or p

rote

asom

al d

egra

datio

n.


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C-4 ALEXANDER ■ HILTON

Fig

ure

4SO

CS

prot

eins

ind

uced

by

one

stim

ulus

can

inh

ibit

sign

alin

g by

sub

sequ

ent

stim

uli.

Age

nts

such

as

LPS

can

stim

ulat

e pr

oduc

tion

of S

OC

S pr

otei

ns.

Onc

e pr

oduc

ed,

thes

e ca

n in

hibi

t si

gnal

ing

indu

ced

by s

ubse

quen

t stim

uli,

such

as

cyto

kine

s, b

y ac

ting

on p

hosp

hory

late

d re

cept

ors

and

JAK

s.


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P1: FRK

February 27, 2004 22:25 Annual Reviews AR210-FM

Annual Review of ImmunologyVolume 22, 2004

CONTENTS

FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg x

GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVESINTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg 1

SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ONDENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet,Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk 33

TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT,Meinrad Busslinger 55

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu 81

LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND,Steven D. Rosen 129

INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila,Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu 157

MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS,AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE,De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski,and Joost J. Oppenheim 181

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGYOF MUCOSAL T CELLS, Hilde Cheroutre 217

THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK,Stephane Wong and Owen N. Witte 247

CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCEAND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind,and Randolph J. Noelle 307

THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn,Lloyd J. Old, and Robert D. Schreiber 329

AUTOIMMUNE AND INFLAMMATORY MECHANISMS INATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu 361

THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama,Sungjin Kim, and Anthony R. French 405

v

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vi CONTENTS

THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMICLUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto,and Mark J. Walport 431

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION ANDRESPONSE, Catherine A. Brennan and Kathryn V. Anderson 457

RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann,and Michel C. Nussenzweig 485

THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS)PROTEINS IN REGULATION OF THE IMMUNE RESPONSE,Warren S. Alexander and Douglas J. Hilton 503

NATURALLY ARISING CD4+ REGULATORY T CELLS FORIMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROLOF IMMUNE RESPONSES, Shimon Sakaguchi 531

PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELLACTIVATION, Jonathan A. Deane and David A. Fruman 563

IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung 599

MOLECULAR DEFECTS IN HUMAN SEVERE COMBINEDIMMUNODEFICIENCY AND APPROACHES TO IMMUNERECONSTITUTION, Rebecca H. Buckley 625

PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE ANDINFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLEFACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky,Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba,Charles Caldwell, Akio Ohta, and Manfred Thiel 657

T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi,David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober 683

IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS,Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda 711

CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS:FUNCTION, GENERATION, AND MAINTENANCE,Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia 745

CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler 765

ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION,Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp 789

CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION,Manfred Brigl and Michael B. Brenner 817

CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASICCHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rotand Ulrich H. von Andrian 891

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CONTENTS vii

INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS,Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter,Yufang Shi, and Paul B. Fisher 929

INDEXESSubject Index 981Cumulative Index of Contributing Authors, Volumes 12–22 1011Cumulative Index of Chapter Titles, Volumes 12–22 1018

ERRATAAn online log of corrections to Annual Review of Immunology chaptersmay be found at http://immunol.annualreviews.org/errata.shtml

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Documents

The Role of Suppressors of Cytokine Signaling (SOCS) Proteins in Regulation of the Immune Response