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Immunology and Cell Biology (2002) 80, 351357
Research Article
Possible mechanism for the alpha subunit of the interleukin-2
receptor (CD25) to influence interleukin-2 receptor signal
transduction
J O N A T H A N M E L L E R Y a n d P E T E R J N I C H O L L
S
Department of Biosciences, University of Kent at Canterbury,
Canterbury, UK
Summary The receptors for interleukin 2 (IL-2) and interleukin
15 (IL-15) in T cells share the IL-2R subunit(CD122) and C subunit
but have private subunits. Despite utilizing the same receptor
chains known to benecessary and sufficient to transduce IL-2
signals the two cytokines manifest different cellular effects. It
iscommonly held that the subunit of the IL-2R (CD25) is involved
solely in the generation of a high affinity receptorcomplex. This
is questioned by the development of autoimmune diseases in
instances where the expression of CD25is absent. The timely
expression of CD25 in the thymus has been linked with clonal
deletion. Evidence fromperipheral T cells indicates that survival
signals arising from the intermediate affinity IL-2R (lacking CD25)
do notrequire the activation of Janus kinase 3 (Jak3) but do
require the presence of the membrane proximal region of theC chain.
This particular signalling pathway is not observed in the high
affinity receptor complex where Jak3 isactivated. Recent data point
to CD25 having a surface distribution consistent with it being
localized withinmembrane microdomains. Here we suggest that in the
absence of CD25 expression, IL-2R activation occurs withinthe
soluble membrane fraction. This membrane environment and the
absence of CD25 promotes Jak3 independentsignal transduction and
induction of antiapoptotic mechanisms. T cell antigen receptor
(TCR) signalling leads to theinduction of CD25 expression, which
localizes to membrane microdomains. There is a dynamic
pre-association ofCD25 and CD122 leading to the loose association
of the heterodimer with membrane microdomains. High affinityIL-2R
signalling in the context of CD25 and the microdomain environment
is characterized by Jak3 activation. Therelative levels of high to
intermediate affinity receptor signalling determines whether a cell
proliferates or undergoesactivation induced cell death dependent
upon cell status.
Key words: CD25, interleukin-2, microdomain, signal
transduction.
Introduction
Interleukin-2 (IL-2) and interleukin-15 (IL-15) are
cytokinesinvolved in the development and survival of T, B and
naturalkiller (NK) cells and, in the generation of immune
responses.The receptors consist of a private alpha subunit and the
sharedbeta (CD122) and common gamma (C) subunits of the
IL-2receptor (IL-2R).1 Heterodimerization of the cytoplasmicdomains
of CD122 and the C subunit are sufficient andnecessary for signal
transduction2 and IL-2 and IL-15 activatesimilar signalling
molecules.3 This explains why IL-15 andIL-2 share some
physiological effects, but does not explainthe different roles that
these two cytokines play in thegeneration of immune cells and their
peripheral responses toantigens.4 Currently CD25 is thought to act
solely to generatethe high affinity IL-2R consisting of the
CD25/CD122/Csubunit heterotrimer, but lack of CD25 expression leads
to adecrease in peripheral T cells and the occurrence of
auto-reactive clones.5,6 Lack of expression of the alpha subunit
ofthe IL-15 receptor (IL-15R) in mice, prevents the develop-ment of
CD8+ or NK cells.7
Signalling through the intermediate affinity IL-2R
Nave T cells do not express CD25 and consequently onlyexpress
the intermediate affinity IL-2R consisting of CD122and the C
subunit. Stimulation of these T cells with IL-2leads to the
induction of a Janus kinase (Jak3) independentsignalling cascade
through the lymphocyte specific tyrosinekinase, p56l ck (lck), to
phosphatidylinositol-3 kinase (PI3-K)and hence to the induction of
antiapoptotic mechanisms.8 Thissignalling cascade was shown to be
dependent upon thepresence of the membrane proximal domain (PROX)
of the Csubunit9 and a possible mechanism for this has been
proposedpreviously.10 The expression of a carboxyl terminal
truncatedC subunit, retaining the PROX domain, in a C subunit
nullmouse background restores T cell development through
theexpression of bcl-2 but the functions of the mature T cellswere
abnormal.11 This would indicate that the C subunit isessential for
T cell development primarily because of its Jak3independent
antiapoptotic signalling cascade.
Ligation of the T cell antigen receptor leads to the induction
of CD25 expression
Engagement of antigen by T cell antigen receptor (TCR) inthe
context of major histocompatability complexes presentedon a cell
surface leads to the formation of a TCR signallingsynapse involving
the clustering of cholesterol-rich micro-domains in the plasma
membrane.12,13 The quaternary complex
Correspondence: Dr PJ Nicholls, Department of
Biosciences,University of Kent at Canterbury, Canterbury CT2 7NJ,
UK. Email: [email protected]
Received 17 December 2001; accepted 21 March 2002.
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352 JM Ellery and PJ Nicholls
formed promotes tyrosine phosphorylation and excludes
thetyrosine phosphatase CD45. Membrane microdomains areimportant in
preventing inappropriate protein interactions inresting T cells but
promote these interactions when the cellsare activated.14 One of
the consequences of TCR signalling isthe induction of CD25,15
IL-15R16 and the up-regulation ofJak3 expression.
CD25 associates with CD122 altering its cell surface
distribution
It has recently been shown that CD25 colocalizes with HLAclass I
and II molecules and with CD48 in a cholesterol-dependent manner17
as well as being isolated in detergent-resistant membranes.18 These
results indicate that when CD25is expressed, it localizes to
microdomains within the plasmamembrane. Structural analysis of the
IL-2R complex in celllines and using surface plasmon resonance
techniques provideexperimental support for the pre association of
CD25 andCD122 as a heterodimer prior to IL-2 binding.19,20 The
inter-action of the cytoplasmic domain of CD122 with that ofCD25
leads to an extracellular conformational change, givingrise to the
increased affinity of the heterodimer for IL-2.21
This raises the possibility that the surface expression
patternof CD122 is altered when it is a component of the
preformedCD25/CD122 heterodimer (Fig. 1). Fluorescence
resonanceenergy transfer (FRET) analysis of the proximities of
CD25,CD122 and the C subunit in Kit225 K6 T lymphoma cells,supports
the notion that all three subunits are already looselyassociated
and that the addition of IL-2 brings the subunitstogether.22 It
must be emphasized that the loose association ofthe high affinity
receptor subunits must be a dynamic onebecause of the different
fates of the subunits upon endocytosis
due to natural turnover or in response to IL-2 ligation. CD25is
recycled to the plasma membrane whilst CD122 and the Csubunit are
predominantly degraded.23,24 The result is anexcess of CD25
molecules, which will promote the looseassociation of CD122 with
microdomains. Excess CD25would also favour the formation and
signalling through highaffinity receptors at the expense of
signalling through inter-mediate affinity receptors. The change in
membrane localiza-tion as well as the change in orientation of the
cytoplasmicdomains25 is likely to have profound effects upon
receptorsignalling. To date there are no data upon the surface
distribu-tion of IL-15R in T cells, but we would predict that it
willnot be found to localize to microdomains.
Signalling through the high affinity IL-2R
Signalling through the high affinity IL-2R is associated withT
cell proliferation and up-regulation of cytotoxic
cellularprocesses. This occurs through a Jak3-dependent
mechanismleading to the activation of a number of different
signaltransducers and activators of transcription (STAT)
molecules.The ability of IL-2 to mediate such effects is
criticallydependent upon the expression and activation of STAT
mole-cules. Lack of STAT3 or STAT5a expression inhibits
theexpression of CD25 in response to either TCR or IL-2signalling,
leading to a failure of IL-2-driven T cell prolifera-tion.26,27
Such observations demonstrate that CD25 plays amore fundamental
role in IL-2R signalling than just thegeneration of a high affinity
receptor form. It has also beenshown that the immobilization of
microdomains by antibodiesagainst molecules such as Thy1 and CD48
prevents highaffinity IL-2R formation, a reduction in Jak1/3
activationstates and the prevention of T cell proliferation.28
Janus
Figure 1 The induction ofCD25 expression upon ligation ofthe TCR
leads to an association ofCD122 molecules with CD25.The heterodimer
becomes local-ized to microdomains within theplasma membrane. ,
plasmamembrane; , CD 25; , micro-domain.
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CD25 and interleukin-2 signal transduction 353
kinase1 and Jak3 were found to be still associated withCD122 and
the C subunit, respectively, but their activationwas reduced.
The strength of antigen signalling will have a direct effectupon
the level of CD25 induction. As the level of inductionincreases,
more of the population of CD122 molecules willbecome associated
with the nascent CD25 and become asso-ciated with microdomains. The
consequent effect is a deple-tion of the number of CD122 present in
the soluble fraction ofthe plasma membrane and thus a reduction in
the levels ofintermediate affinity IL-2Rs. Matk et al. have shown
thathigh affinity IL-2Rs localize to microdomains and
theirdisruption by cholesterol depletion impaired STAT
activa-tion.29 This at first appears to be at odds with the
findings ofMina and Julius who used Brij58 to isolate the
detergent-resistant microdomains.30 In both cases CD25 was found
tolocalize to microdomains. The differences in opinion withregards
the localization of CD122 and the c subunit are areflection upon
the loose peripheral association that thesemolecules have with the
detergent-resistant membrane frac-tion. Different techniques will
lead to either a disruption orstrengthening of the association. In
the scenario that wepresent here, just as intermediate affinity
IL-2Rs are incap-able of Jak3-dependent signal transduction, high
affinity IL-2Rs are not capable of generating Jak3-independent
antiapop-totic signals. This is not an unrealistic situation, as
thereappears to be a clear delineation between signalling
mole-cules that are activated by Jak3 or by lck.31 For T cells
tosurvive, a threshold level of intermediate affinity IL-2Rs needto
be maintained. Below this threshold, cells become suscept-ible to
activation-induced cell death (AICD) in the absence ofother
costimulatory survival signals. Here then is a mecha-nism which can
be used to explain how a T cell will react to agiven antigen.
A very high affinity/avidity interaction with a target cellwill
lead to aggregation of microdomains and sequestering ofCD25. The T
cell does not proliferate but also does notundergo apoptosis
because CD122 and the C subunit can stillform a functional
intermediate IL-2R. This makes sensebecause a T cell that interacts
too strongly with its target willnot be an efficient agent of the
immune system because itwill not be able to repeatedly disengage
and re-engageantigen-bearing cells. T cells demonstrating no
interactionwill retain intermediate affinity IL-2Rs and remain
viable butwill not proliferate. The remaining T cells which
interact withthe target antigen will do so with a spectrum of
affinity andavidity. TCR induction of CD25 will promote the
formationof high affinity IL-2Rs provided that microdomains are
notimmobilized within the plasma membrane. The level to whichthis
occurs will determine the relative levels of high andintermediate
affinity IL-2Rs and thus the amount of prolifera-tive and survival
signal generated within a T cell clone. Toostrong an interaction
will lead to CD25 sequestering CD122and the C subunit into high
affinity IL-2Rs because themicrodomains remain mobile and also
because of a corre-sponding lack of intermediate affinity IL-2Rs.
Thus one of thefirst decisions that influences whether a T cell
will eitherbecome anergic or proliferative or undergo apopotosis,
i.e.ACID, in response to TCR engagement can be dependentupon the
level of CD25 induction and the extent to whichmicrodomains
aggregate (Fig. 2). Signalling through high
affinity IL-2Rs also causes an increase in FasL expressionand a
decrease in C subunit expression with a subsequentknock-on effect
upon bcl-2 induction.32 Cells can be rescuedfrom AICD by other
cytokines, which are still able to supplythese signals, such as
IL-15.33 It is clear that as T cells down-regulate IL-2R
expression34 other costimulatory pathwaysbecome more important for
long-term activated T cell function.
The role of Jak3 in T cell development
A number of researchers have shown that in mouse knockoutmodels
of Jak3, the phenotype is the same as that for Csubunit knockouts.
It is difficult to determine the exactmechanism that is at work
here because of the large numberof cytokines utilizing the C
subunit and Jak3 for signaltransduction. The phenotype is
essentially manifested as asevere reduction in mature T cell
populations and an inabilityto delete auto-reactive clones in the
thymus and peripheraltissues.35 The reduction in lymphoid cells is
attributed to theapoptosis of thymocytes by elevated levels of Bax
andreduced levels of Bcl2 in Jak3-deficient T cells. These cellscan
in part be rescued by transduction with a Bcl2
expressingretrovirus.36 Interleukin-7 is a cytokine that utilizes
the Csubunit as a component of its receptor and is known to
beimportant for T cell development. Mouse models lackingeither
IL-7, IL-7R or Jak3 display a near absence of thymicprogenitor
cells.37,38 The finding that Jak3 provides survivalsignals has been
taken as evidence to support the proposalthat Jak3-independent
survival signals are not relevant. Inter-estingly Jak3 null mice
did not generate CD25+ CD4+ Tcells.39 The vastly reduced number of
thymic progenitor cellswould point to the requirement of
Jak3-dependent cytokinesignalling before any effect that CD25 may
have in clonaldeletion. Thus Jak3 survival signals may be
generatedthrough cytokine receptors that utilize the c subunit
otherthan IL-2 at specific times during the developmental
process.In turn the role that CD25 plays will be but one aspect of
theentire process and will be relevant in a particular cell
context.
Differences between the biological effects of IL-2 and IL-15
explained
The finding in IL-15 transgenic mice that IL-2-induced AICDis
inhibited highlights the differences in signal transductionbetween
these two cytokines.32 There are clearly differencesin the way that
the high affinity receptors bind their cytokineligands. Data
indicate that CD25 pre-associates with CD122and together they
capture IL-2 simultaneously before recruit-ing the C subunit.
Interleukin-15R has a very high affinityfor IL-15 independent of
CD122. Once IL-15 has been boundthe complex then recruits CD122 and
IL-2RC. The binding ofIL-15 by CD122 and the C subunit is different
and cannot beinhibited by IL-2.40 There are also differences in the
inter-action of the alpha subunits with CD122 and the C
subnuit.41We postulate that the differences in the interaction of
thealpha subunits provide the basis for the alternate
signallingpathways observed. CD25 appears to be essential for
Jak3-dependent IL-2 signalling but we predict that this is at
theexpense of Jak3-independent antiapoptotic signalling. Thehigh
affinity IL-15R on the other hand, generates both typesof
signalling cascade. The role that microdomains play is an
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354 JM Ellery and PJ Nicholls
added dimension in the control of IL-2R signalling and wepredict
that such an association is not required for IL-15Rfunction. The
different cellular effects of IL-2 and IL-15 canbe explained by the
interaction of their alpha receptor sub-units and the localization
of CD25 in microdomains.
Interleukin-15R can bind tumour necrosis factor
receptor-associated factor 2 (TRAF2) and possibly protect
againstcertain receptor-mediated apoptotic pathways. Through
TRAF2,IL-15 is able to activate the transcription factor NF-B42
although the consequences of this are not fully
understood.Crucially, because the high affinity IL-15R resides
outside ofmicrodomains it maintains Jak3-independent
antiapoptoticsignalling. The stability of the receptor complex and
itsorientation are such that Jak1 and Jak3 also become activatedand
lead to proliferative signal transduction (Fig. 3).
Thushigh-affinity IL-15 signalling provides both proliferative
andprotective signals unlike CD25-associated IL-2 signallingwhich
can be involved in the negative regulation of cell
Figure 2 The role of microdomains in IL-2R signalling. The
number of high affinity IL-2Rs formed influence the strength of
IL-2 Januskinase 3 (Jak3)-dependent signal transduction leading to
cellular proliferation. If the consequent reduction in the number
of intermediateaffinity IL-2Rs falls below a threshold there will
be insufficient Jak3-independent antiapoptotic signal transduction.
Over-expression ofCD25 may lead to a critical lack of intermediate
affinity receptors exposing the cell to possible activation-induced
cell death (AICD).Sequestering of CD25 by microdomain
immobilization will prevent the formation of high affinity IL-2R
and a subsequent reduction inJak3-dependent cell proliferation. ,
CD 122; , plasma membrane; , CD 25; , microdomain.
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CD25 and interleukin-2 signal transduction 355
expansion.43 In fact the expression of CD25 appears to
becritical for clonal deletion and avoidance of
autoimmunediseases44 both in the thymus and periphery.45 The
pivitol rolethat CD25 plays in clonal deletion within the thymus
wasconfirmed by blockade. T cell antigen receptor stimulation
ofthymocytes led to the expression of CD25 and IL-2. Thesubsequent
AICD in some thymocytes could be prevented byantibody blockade of
CD25.46 In our proposed scenario thosethymocytes that could be
rescued still retained intermediateaffinity IL-2Rs. These could
provide antiapoptotic signalswhen the high affinity receptors were
blocked. For example,over-expression of bcl-2 in transgenic mice
can prevent clonaldeletion.47 This is a clear indication that CD25
is involved inthe prevention of antiapoptotic signalling through
the IL-2Rand we believe that this is mediated through a change
inreceptor compartmentalization and subunit orientation withinthe
receptor complex.
Conclusion
Although the receptors for IL-2 and IL-15 share CD122 andthe C
subunit they have different cellular effects and contrast-ing roles
within the body. In this paper we have put forward amechanism to
explain how the private alpha subunits of thereceptors mediate
these differences. The intermediate affinity
form of the IL-2R (lacking CD25) is located primarily in
thesoluble subcompartment of the plasma membrane. Signallingthrough
this receptor form under normal conditions is medi-ated by a
Jak3-independent mechanism and is antiapoptotic.Expression of CD25,
in response to TCR engagement, leadsto preferential association
with CD122 and subsequentlyleads to CD122 being loosely associated
with microdomains.The level of CD25 induction determines the
proportion ofCD122 that becomes associated with microdomains. In
thecontext of CD25 and the microdomain environment, thepredominant
signalling cascade from the high affinity IL-2Ris Jak3 dependent.
Just as the presence of CD25 in thereceptor complex alters the
binding of IL-2 by CD122 it islikely to alter the orientation of
the cytoplasmic domain ofCD122 as well. It is this interaction we
believe that effec-tively leads to the loss of the protective
Jak3-independentsignalling. Cell proliferation and survival are
dependent uponthe relative levels of signalling through high and
intermediateaffinity IL-2Rs. A depletion of intermediate affinity
IL-2Rwill lead to susceptibility to AICD due to a lack of
survivalsignals. The high affinity IL-15R does not localize to the
micro-domain. Interleukin-15R binds IL-15 with high affinity
andthen binds CD122 and the C subunit in a manner whichprevents
IL-2 binding. The resultant signalling comprisesboth proliferative
and protective elements. Thus the private
Figure 3 Interleukin-15 signalling occurs outside of
microdomains. The ability of IL-15R to bind tumour necrosis factor
receptor-associated factor 2 (TRAF2) coupled with activation of
Janus kinase 3 (Jak3)-independent antiapoptotic signalling protects
againstactivation induced cell death (AICD). The orientation of the
receptor complex and its stability allows Jak1/Jak3 activation to
promotecell proliferation. , IL-15R; , CD122, , IL-2Rc.
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356 JM Ellery and PJ Nicholls
alpha chains play a pivitol role in controlling the response ofa
cell to IL-2 and IL-15. The compartmentalization of CD25provides an
additional level of regulation to IL-2, in responseto the type of
stimuli the T cell has encountered.
References1 Giri JG, Ahdie M, Shanebeck K et al. Utilization of
the beta and
gamma chains of the IL-2 receptor by the novel cytokine
IL-15.EMBO J. 1994; 13: 282230.
2 Nakamura Y, Russell SM, Mess SA et al. Heterodimerization
ofthe IL-2 receptor beta and gamma chain cytoplasmic domains
isrequired for signalling. Nature 1994; 369: 3303.
3 Johnston JA, Bacon CM, Finbloom DS et al. Tyrosine
phosphor-ylation and activation of STAT5, STAT3, and Janus kinases
byinterleukins 2 and 15. PNAS 1995; 92: 87059.
4 Lorenz HM, Hieronymus T, Grunke M, Manger B, Kalden
JR.Differential role for IL-2 and IL-15 in the inhibition of
apoptosisin short-term activated human lymphocytes. Scand. J.
Immunol.1997; 45: 6609.
5 Sharfe N, Harijit KD, Shahar M, Roifman CM. Human
immunedisorder arising from mutation of the chain of the
interleukin-2receptor. PNAS 1997; 94: 316871.
6 Roifman CM. Human IL-2 receptor alpha chain
deficiency.Pediatr. Res. 2000; 48: 611.
7 Lodolce JP, Boone DL, Chai S et al. IL-15 receptor
maintainslymphoid homeostasis by supporting lymphocyte homing
andproliferation. Immunity 1998; 9: 66976.
8 Gonzalez-Garcia A, Merida I, Martinez AC, Carrera AC.
Inter-mediate affinity interleukin-2 receptor mediates survival via
aphosphatidylinositol 3-kinase-dependent pathway. JBC 1997;272: 10
2206.
9 Tsujino S, Miyazaki T, Kawahara A, Maeda M, Taniguchi T,Fujii
H. Critical role of the membrane-proximal, proline-richmotif of the
interleukin-2 receptor gamma c chain in the Jak3-independent signal
transduction. Genes Cells 1999; 4: 36373.
10 Ellery JM, Kempshall SJ, Nicholls PJ. Activation of the
inter-leukin 2 receptor: a possible role for tyrosine phosphatases.
Cel-lular Signalling 2000; 12: 36773.
11 Tsujino S, Di Santo JP, Takaoka A et al. Differential
require-ment of the cytoplasmic subregions of C chain in T cell
develop-ment and function. PNAS 2000; 97: 10 51419.
12 Viola A. The amplification of TCR signaling by dynamic
mem-brane microdomains. Trends Immunol. 2001; 22: 3227.
13 Miceli MC, Moran M, Chung CD, Patel VP, Low T, Zinnanti
W.Co-stimulation and counter-stimulation; lipid raft clustering
con-trols TCR signaling and functional outcomes. Semin.
Immunol.2001; 13: 11528.
14 Janes PW, Ley SC, Magee AI, Kabouridis PS. The role of
lipidrafts in T cell antigen receptor (TCR) signalling. Semin.
Immu-nol. 2000; 12: 2334.
15 Szamel M, Appel A, Schwinzer R, Resch K. Different
proteinkinase C isoenzymes regulate IL-2 receptor expression or
IL-2synthesis in human lymphocytes stimulated via the TCR.
J.Immunol. 1998; 160: 220714.
16 Chae DW, Nosaka Y, Strom TB, Maslinski W. Distribution
ofIL-15 receptor alpha-chains on human peripheral blood
mono-nuclear cells and effect of immunosuppressive drugs on
receptorexpression. J. Immunol. 1996; 157: 281319.
17 Vereb G, Matk J, Vmosi G et al. Cholesterol-dependent
clus-tering of IL-2R and its colocalization with HLA and CD48 onT
lymphoma cells suggest their functional association with
lipidrafts. PNAS 2000; 97: 601318.
18 Field KA, Holowka D, Braid B. Structural aspects of the
associa-tion of FcRI with detergent-resistant membranes. JBC
1999;274: 17538.
19 Landgraf BE, Goldstein B, Williams DP et al.
Recombinantinterleukin-2 analogs. Dynamic probes for receptor
structure.JBC 1992; 267: 18 51119.
20 Myszka DG, Arulanantham PR, Sana T, Wu Z, Morton TA,Ciardelli
TL. Kinetic analysis of ligand binding to interleukin-2receptor
complexes created on an optical biosensor surface.Protein Sci.
1996; 5: 246878.
21 Goldsmith MA, Amaral MC, Greene WC. Ligand binding by theIL-2
receptor is modulated by intracellular determinants of theIL-2
receptor beta chain. J. Immunol. 1995; 154: 203340.
22 Damjanovich S, Bene L, Matko J et al. Pre-assembly of
inter-leukin 2 (IL-2) receptor subunits on resting Kit 225, K6 T
cellsand their modulation by IL-2, IL-7, and IL-15: A
fluorescenceresonance energy transfer study. PNAS 1997; 94:
131349.
23 Hemar A, Subtil A, Lieb M et al. Endocytosis of interleukin
2receptors in human T lymphocytes: distinct intracellular
localiza-tion and fate of the receptor alpha, beta, and gamma
chains. J.Cell. Biol. 1995; 129: 5564.
24 Rocca A, Lamaze C, Subtil A et al. Involvement of the
ubiquitin/proteasome system in sorting of the interleukin 2
receptor chain to late endocytic compartments. Mol. Biol. Cell
2001; 12:1293301.
25 Syed RS, Reid SW, Li C et al. Efficiency of signalling
throughcytokine receptors depends critically on receptor
orientation.Nature 1998; 395: 51116.
26 Akaishi H, Takeda K, Kaisho T et al. Defective
IL-2-mediatedIL-2 receptor alpha chain expression in
Stat3-deficient lym-phocytes. Int. Immunol. 1998; 10: 174751.
27 Nakajima H, Liu XW, Wynshaw-Boris A et al. An indirect
effectof Stat5a in IL-2-induced proliferation: a critical role for
Stat5ain IL-2-mediated IL-2 receptor alpha chain induction.
Immunity1997; 7: 691701.
28 Marmor MD, Bachmann MF, Ohashi PS, Malek TR, Julius
M.Immobilization of glycosylphosphatidylinositol-anchored pro-teins
inhibits T cell growth but not function. Int. Immunol. 1999;11:
138193.
29 Matk J, Bodnr A, Vereb G et al. GPI-microdomains (mem-brane
rafts) and signalling of the multi-chain interleukin-2receptor in
human lymphoma/leukaemia T cell lines. Eur. J. Bio-chem. 2002; 269:
1199208.
30 Marmor MD, Julius M. Role for lipid rafts in
regulatinginterleukin-2 receptor signalling. Blood 2001; 98:
148997.
31 Zhou Y-J, Magnuson KS, Cheng TP et al. Hierarchy of
proteintyrosine kinases in interleukin-2 (IL-2) signalling:
Activation ofSyk depends on Jak3; however, neither Syk nor Lck is
requiredfor IL-2-mediated STAT activation. Mol. Cell Biol. 2000;
20:437180.
32 Dai Z, Arakelov A, Wagener M, Konieczny BT, Lakkis FG.
Therole of the common cytokine receptor -chain in regulating
IL-2-dependent, activation-induced CD8= T cell death. J.
Immunol.1999; 163: 31317.
33 Marks-Konczalik J, Dubois S, Losi JM et al.
IL-2-inducedactivation-induced cell death is inhibited in IL-15
transgenicmice. PNAS 2000; 97: 11 44550.
34 Duprez V, Cornet V, Dautry-Varsat A. Down-regulation of
highaffinity interleukin 2 receptors in a human tumor T cell line.
JBC1988; 263: 12 8605.
35 Saijo K, Park SY, Ishida Y, Arase H, Saito T. Crucial role
ofJak3 in negative selection of self-reactive T cells. J. Exp.
Med.1997; 185: 3516.
-
CD25 and interleukin-2 signal transduction 357
36 Wen R, Wang D, McKay C et al. Jak3 selectively regulates
Baxand Bcl-2 expression to promote T-cell development. Mol.
CellBiol. 2001; 21: 67889.
37 Baird AM, Lucas JA, Berg LJ. A profound deficiency in
thymicprogenitor cells in mice lacking Jak3. J. Immunol. 2000;
165:36808.
38 Eynon EE, Livk F, Kuida K, Schatz DG, Flavell RA.
Distincteffects of Jak3 signalling on and thymocyte development.J.
Immunol. 1999; 162: 144859.
39 Suzuki K, Nakajima H, Saito Y et al. Janus kinase 3 (Jak3)
isessential for common cytokine receptor chain (c)
-dependentsignalling: comparative analysis of c, Jak3, and c and
Jak3double-deficient mice. Int. Immunol. 2000; 12: 12332.
40 Lehours P, Raher S, Dubois S, Guo J, Godard A, Jacques
Y.Subunit structure of the high and low affinity human
interleukin-15 receptors. Eur. Cytokine Netw. 2000; 11: 20715.
41 de Jong JL, Farner NL, Sondel PM. Distinctions in
lymphocyteresponses to IL-2 and IL-15 reflect differential ligand
bindinginteractions with the IL-2Rbeta chain and suggest
differentialroles for the IL-2Ralpha and IL-15Ralpha subunits.
Cytokine1998; 10: 92030.
42 Pereno R, Giron-Michel J, Gaggero A et al.
IL-15/IL-15Ralphaintracellular trafficking in human melanoma cells
and signal trans-duction through IL-15Ralpha. Oncogene 2000; 19:
515363.
43 Leclercq G, Debacker V, de Smedt M, Plum J.
Differentialeffects of interleukin-15 and interleukin-2 on
differentiation ofbipotential T/natural killer progenitor cells. J.
Exp. Med. 1996;184: 32536.
44 Kung JT, Beller D, Ju ST. Lymphokine regulation of
activation-induced apoptosis in T cells of IL-2 and IL-2R beta
knockoutmice. Cell. Immunol. 1998; 185: 15863.
45 Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt
FW.Interleukin-2 receptor chain regulates the size and content of
theperipheral lymphoid compartment. Immunity 1995; 3: 52130.
46 Bassiri H, Carding SR. A requirement for il2/il2
receptorsignalling in intrathymic negative selection. J. Immunol.
2001;166: 594554.
47 Siegel RM, Katsumata M, Miyashita T, Louie DC, Greene MI,Reed
JC. Inhibition of thymocyte apoptosis and negative anti-genic
selection in bcl-2 transgenic mice. PNAS 1992; 89:70037.
