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Regulation in mice
of protective immunity against Leishmania
459
major
Jacques Louis *, Hayo Himmelrich, Carlos Parra-Lopez, Fabienne Tacchini-Cottier and Pascal Launois
Resolution of lesions induced by Leishmania major in mice
results from the development of Thl responses. Cytokines
produced by Th 1 cells activate macrophages to a
parasiticidal state. The development of Th2 responses in
mice from a few strains underlies susceptibility to infection.
Cytokines produced by Th2 cells exacerbate the
development of lesions because of their deactivating
properties for macrophages. This murine model of infection
has provided significant insight into the mechanisms intrinsic
to the differentiation of disparate CD4+ T cell subsets in viva
in animals from different genetic backgrounds.
Addresses
WHO Immunology Research and Training Center, Institute of
Biochemistry, University of Lausanne, 155 Chemin des Boveresses,
CH-1066, Epalinges, Switzerland
*e-mail: [email protected]
Correspondence: Jacques Louis
Current Opinion in Immunology 1998, 10:459-464
http://biomednet.com/elecref/0952791501000459
0 Current Biology Publications ISSN 0952-7915
Abbreviations
FasL Fas ligand
IFN-y interferon-y
IFN-yR interferon-y receptor
iNOs inducible nitric oxide synthase
IRFl interferon regulatory factor 1
LACK Leishmania-activated C kinase
NK natural killer
TNF-u tumor necrosis factor CL
Introduction hlice from the majority of inbred strains (CS7BL/6,
CXH/He, SvlZY/Ev, etc) are resistant to infection with the
intracellular pathogen, Lt%A~lanlu majur. In contrast mice
from a few strains, such as BALB/c, develop progressive
lesions, that never heal, and remain susceptible to rein-
fection. This genetically determined resistance and sus-
ceptibility to infection with this parasite has been
demonstrated to result from the development of specific
CD4+ Thl or TM responses, respectively [l]. In this
short review, we have summarized recent findings
obtained using this murine model of infection pertaining,
firstly, to the immune effector mechanisms capable of
restricting the growth of L. )tzaJor in resistant mice; sec-
ondly, to the downregulation of these protective immune
responses in susceptible mice leading to progressive dis-
ease; and, thirdly, to the mechanisms mediating differen-
tiation of disparate CD4+ T cell subsets in mice from
different genetic backgrounds.
Acquired protective immune effector mechanisms Healing of lesions induced by L. wajw- requires the induc-
tion and expansion of specific CD4+ Thl cells that are
restricted by MHC class 11 and produce interferon-y
(IFN-y). This cytokine activates the inducible nitric oxide
synthase (iNOs) in macrophages leading to the production
of reactive nitrogen radicals that is dependent on L-argi-
nine and is toxic for intracellular L. /n&r [Z]. The role of
IFN-y in the control of infection with L. mt+or was firmly
established by results showing that genetically resistant
mice with disrupted genes for IFN-)I or IFN-y receptor
(IFN-yR) [3,4] failed to resolve their lesions.
The importance of the nitric-oxide-dependent pathway of
cytotoxicity for the killing of intracellular parasites was
demonstrated by results showing that resistant mice, either
treated with inhibitors of iXOs or deficient for the gene
that encodes iNOs, failed to contain infection [S]. It is well
known that L. wu~jiw persists, in low numbers, even in resis-
tant mice that have resolved their cutaneous lesions.
Reactive nitrogen radicals also play a role in keeping this
quiescent status since treatment of resistant CS7BL/6 mice
with an inhibitor of iNOs, at a time when cutaneous lesions
are resolved, resulted in an expansion of parasites that had
been either quiescent or replicating slowly [6]. Recently,
using mice genetically deficient for the gene encoding
iNOs, it was further shown to control the activity of natur-
al killer (NK) cells and the early cytokine response (IFN-7,
IL-12 and transforming growth factor /3) during the first 24
hours of infection with L. MU&I. [7’], thereby playing a crit-
ical regulatory role on the innate response to this parasite.
Even though IFN-U/B induced by L. t~qbr i/l d-o is
required for the initial expression of iNOs [7’], mice lack-
ing the genes for IFN-yor the IFN-yR, with normal expres-
sion of IFN-a/P, are not able to produce nitric oxide in
response to various stimuli, suggesting that IFN-y is a cru-
cial inducer of the activation of iNOs [8,9].
The cytotoxicity mediated by CD4+ Thl cells & aitro
requires a functional Fas (APO-l, CD95) pathway [lo]. In
contrast to wild-type CS7BL/6 (resistant) mice, CS7BL/h
g/d or /pr mice lacking either a functional Fas or Fas ligand
(FasL) are unable to resolve lesions induced by L. wajw in
spite of the fact that tile!- develop a CD4+ Thl response
and that their macrophages produce normal levels of reac-
ti1.e nitrogen radicals in response to IFN-y ill cifro [ll’].
Administration of exogenous recombinant FasL to FasL-
deficient CS7BL/6 &f mice resulted in the resolution of
lesions, demonstrating the importance of the Fas-FasL
pathway in the elimination of parasires: furthermore.
460 Immunity to infection
macrophages infected with L. major up-regulated their sur-
face expression of Fas in response to IFN-y and as a result
became susceptible to apoptotic death induced by CD4+
Thl cells [ll’]. It is thus possible that apoptosis of Fas-
expressing macrophages at the site of infection causes a
limitation in the number of the host cells necessary for par-
asite replication (i.e. macrophages) and thereby increases
the ratio of IFN-y-producing CD4+ Thl cells to infected
macrophages, therefore increasing the efficiency of
macrophage activation to a microbicidal stage.
Acquired immune effector mechanisms underlying susceptibility to infection It is now well accepted that the susceptibility to infection
that characterizes mice of the BALB strains results from
the development of a Th2 response. Recently, a stable
cell-surface molecule, STLZ, has been described, that dis-
tinguishes Th2 from Thl cells [12]. Cytokines produced
by Th2 cells exert a macrophage-deactivating function
[13]. IL-4 has indeed been shown to hamper the activation
of macrophages induced by IFN-y and to suppress the
upregulation of gene expression mediated by IFN-y, par-
ticularly the gene for interferon regulatory factor 1 (IRF-1)
[14’]. Transforming growth factor p, IL-10 and IL-13 are
also able to interfere with the induction of iNOs that is
triggered by IFN-y [13,15].
Innate immune effector mechanisms NK cells have an important role early in infection process-
es since, unlike naive T cells, they respond very rapidly to
stimuli and do not require priming [16,17”]. NK cells pro-
duce a wide range of cytokines such as IFN-y and TNF-cx
which inhibit the growth of pathogens during the initial
stage of infection, thus allowing the host to develop an effi-
cient adaptive immune response. Importantly, these cells
could also play a role in shaping the adaptive response, par-
ticularly by influencing the pathway of differentiation of
CD4* T cells. The effector function of NK cells and their
role in the generation of a Thl response during infection
with L. major has been suggested, by results showing that
depletion of NK cells in resistant mice favours parasite
multiplication in lesions [18]. This treatment also
decreased the IFN-y production normally seen in resistant
mice and increased the IL-4 response. Mice that do not
express the transcription factor IRF-1 have been shown to
be defective in NK cell function [19,20’]. Resistant mice
deficient for the IRF-1 molecule were susceptible to infec-
tion with L. major and mounted an aberrant CD4+ ThZ cell
response, thus indicating that IRF-1 is a factor implicated
in Thl responses [Zl’]; furthermore the successful vacci-
nation of susceptible BALB/c mice with an extract of
L. major and IL-12 required the presence of NK cells [Z!].
In addition to its Thl-promoting effect on CD4+ T cell pre-
cursors, IL-12 activates NK cells to produce IFN-)I. In this
context, it has been proposed that IL-12 also favours Thl
cell development through its capacity to stimulate IFN-y
production by NK cells; however, following infection with
L. major, early IL-12 production and activation of NK cells
are not seen in all strains of resistant mice, rather suggest-
ing that IFN-y production by NK cells is not essential for
Thl cell differentiation [23].
The differentiation of distinct CD4+ T cell subsets in differing mouse strains following infection with Leishmania major Thl and Th2 CD4+ T cells develop from a common naive
CD4+ T cell precursor and several parameters have been
reported to influence the pathway of differentiation of
CD4+ T cell precursors [ 131.
Role of accessory molecules The CD40 molecule and its ligand, as well as CD80 (B7-
1) and CD86 (B7-Z), play a role in the differentiation of
CD4+ T cells after infection with L. major and conse-
quently in the outcome of disease. Resistant mice defi-
cient in either the CD40 or CD40-ligand molecules and
infected with L. major or L. amazonensis fail to mount a
vigourous Thl response and are unable to control infec-
tion [24-261; furthermore, blockade of CDS6 with a spe-
cific antibody ameliorated the infection in BALB/c mice
and inhibited ThZ cell development [27]. It is noteworthy
that BALB/c mice deficient in CD28 remain susceptible
to infection [ZS]. Results from recent elegant experiments
strongly suggest that the interaction between the MHC
class II and the CD4 molecule also plays a role in Th2 cell
development [29”,30”].
The role of cytokines The crucial role of cytokines in directing CD4+ T cell dif-
ferentiation has been established in oitro using naive
CD4+ T cells from mice transgenic for TCR-a and -p
chains. In this system, IL-12 and IFN-y were implicated
in Thl cell maturation whereas IL-4 was implicated in
Th2 cell development [13,31]. Cofactors such as IL-l-a
and IL-18 are also required for the development of a Thl
response [32,33”,34,35].
Studies using neutralizing anti-IL-4 antibodies or mice
with disruption of the gene encoding IL-4 have defined a
critical role for this cytokine in mediating the differentia-
tion of the Th2 subset in vlvo and the failure of BALB/c
mice to control L. major infection 1361. In this context, we
have carefully examined IL-4 mRNA expression in both
genetically susceptible BALB/c and resistant C57BL/6
mice during the first seven days of infection with L. major. Within one day of infection, BALB/c mice exhibited a
peak of IL-4 mRNA expression in the draining lymph
nodes. This returned to baseline levels by 48 hours [37].
From day five, a second wave of IL-4 mRNA was observed
that remained elevated during the entire course of infec-
tion and reflected Th2 cell differentiation. No IL-4 mRNA
expression was seen in resistant mice during the first two
days of infection and although low levels of IL-4 produc-
tion were seen five days after infection they returned to
baseline levels seven days after infection [37]. The early
Regulation of protective immunity against Leishmania major in mice Louis et al. 461
IL-4 production in BALB/c mice was not due to activation
of NKl. l+ CD4+ T cells [37] that have been shown to con-
tribute rapidly substantial amounts of IL-4 in &o under
other conditions [38,39]. These NKl.l+ T cells were fur-
ther shown not to play a role in susceptibility to infection
[40,41]; rather, early IL-4 transcription in BALB/c mice
occured in a highly restricted subpopulation of CD4+
T cells that expressed the TCR VP4 and Va8 chains [42”].
The contribution of these cells to the early burst of IL-4
mRNA expression in BALB/c mice in response to infec-
tion was confirmed by results showing that this response
was absent in BALB/c mice rendered selectively deficient
in the Vp4+ CD4+ T cell population [42”]. The
Vp4+ Va8+ CD4+ T cells that produce IL-4 rapidly in
response to L. major are specific for a single antigen of the
parasite called LACK (Leishmanla-activated C kinase;
[42”]) that has been previously identified as an important
antigen recognized by CD4+ T cells in mice infected with
L. major [43].
Clear evidence was obtained that the IL-4, produced by
these Vp4+ VaS+ CD4+ T cells within one day of infection,
plays an essential role in the Th2 differentiation that
occurs in BALB/c mice at a later stage of infection -
among CD4+ T cells no longer restricted to those utilizing
this particular TCR [44’]. Indeed VP4-deficient mice
mounted a polarized Thl response and were fully resistant
to infection [42”]. Thus it appears that a single epitope of
the LACK antigen drives the early IL-4 response by a
restricted population of CD4+ T cells and instructs subse-
quent Th2 differentiation and susceptibility to infection.
This conclusion is in agreement with results from elegant
experiments that have shown that transgenic BALB/c mice
expressing the LACK antigen in the thymus were tolerant
to this antigen and resistant to infection with L. mujor [45].
The essential role of IL-12 in Thl development has been
confirmed in vivo using the murine model of infection with
L. major. Neutralisation of IL-12 in resistant mice allows
the development of a Th2 response [46]. In addition, mice
from a resistant background in which the IL-12 gene had
been deleted develop a Th2 response [47] and suffer from
progressive disease [48]. In complementary studies, exoge-
nous IL-12 given during the first week of infection to sus-
ceptible BALB/c mice resulted in the development of Thl
response and allowed the resolution of lesions [49,50].
Treatment with anti-IL-4 antibodies of resistant mice, that
have been rendered susceptible to infection by treatment
with anti-IL-12 antibodies, allows the resolution of lesions
[46]; this indirectly indicates that one effect of IL-12 is to
reduce IL-4 production. The increased IL-4 mRNA
expression normally observed in draining lymph nodes of
IFN-y-knockout C57BL/6 mice five days after infection
with L. major was indeed readily down-regulated by
exogenous IL-12 [Sl]; this also demonstrates that the
effect is independent of IFN-y. The timing of production
of IL-12 following infection with L. major is still a matter
of debate [S&53]. Results from one study [SZ] have shown
that IL-12 mRNA expression in vivo is delayed up to seven
days after infection, suggesting that the initial steps of
CD4+ T cell differentiation occur in the absence of this
cytokine. This would allow the expression of other genet-
ic tendencies of CD4+ T cell differentiation along a partic-
ular pathway. Downregulation of the IL-12 production that
occurs after ligation of macrophage receptors [54’], partic-
ularly of complement receptor 3, has recently been
demonstrated [SS’]. Since complement receptor 3 is a
potential receptor for the entry of Leishania in
macrophages these results might explain the inhibition of
IL-12 production in macrophages infected with Leishmania
promastigotes [S&53,56].
Recent results obtained using CD4+ T cells transgenic for
TCR-a and -p chains have shown that, in contrast to
BlO.DZ CD4+ T cells, BALB/c CD4+ T cells (that mature
into Th2 effector cells after priming in vitro under neutral
conditions, i.e. in the absence of exogenous cytokines)
rapidly lose their responsiveness to IL-12 during priming
[57,58]. BlO.DZ mice being resistant to infection with
L. major, a model of resistance based on the maintenance
of the IL-12 signaling pathway has been proposed [58,59].
A single locus named Tmp-2 (T-cell modifier phenotype-l)
controls the responsiveness to IL-12 itz vitro and was
mapped to murine chromosome 11, that also contains the
genes for IL-4, IL-S, IL-3 and IRF-1 [60]. The murine IL-
12R is a heterodimer composed of two chains, the IL-
12Rpl and IL-12RP2 [61] which are expressed only in
T cells that have engaged their TCRs [62”]. Extinction of
IL-12 signaling during priming itz vitro of BALB/c CD4+
T cells that are transgenic for TCR-a and -p chains result-
ed from a selective loss of IL-12RP2-chain expression
[62”]. which is necessary for IL-12 signaling through the
Jak/STAT pathway [62”]. The detectable amounts of IL-
4 produced by BALB/c CD4+ T cells during priming under
neutral conditions (i.e. in absence of exogenous cytokines;
[SS]) could inhibit IL-12RP2 chain expression, since addi-
tion of exogenous IL-4 during priming of BlOD2 CD4+
T cells itz vitro was shown to inhibit their responsiveness to
IL-12 [62”].
Within this context we have observed that from 48 hours
and at least up to seven days after infection with L. major,
CD4+ T cells from BALB/c mice become totally unre-
sponsive to IL-12, in contrast to CD4+ T cells from resis-
tant CS7BL/6 mice [44’]. The in vivo induction of this
unresponsive state to IL-12 in the BALB/c CD4+ T cells
resulted from the IL-4 that was produced during the first
day of infection. Recent results from our laboratory have
shown that the expression of the IL-12RP2 chain, which
was induced on CD4+ T cells of both CS7BL/6 and
BALB/c mice within 24 hours of infection with L. major, was readily down-regulated only on CD4+ T cells from
BALB/c mice and occurred as soon as 48 hours after infec-
tion; this effect resulted from the early IL-4 response of
BALB/c mice to infection (H Himmelrich, C Parra-Lopez,
F Tacchini-Cottier, JA Louis, P Louis, unpublished data).
462 Immunity to infection
Although IFN-)I was found to be necessary for the matura-
tion of CD4+ T cells transgenic for TCR-a and -p chains
towards the Thl phenotype in several studies (for example
[63]), its requirement has not always been observed
[64,65]. The demonstration that IFN-yis able to rescue the
IL-4-mediated inhibition of IL-1ZRPZ chain expression by
CD4+ T cells differentiating i?z ~itr-o [62”], provides a
rational basis for this discrepancy. Indeed, when IL-4 is
produced during priming ilz z&m, IFN-)I is necessary to
permit the IL-12 signaling required for Thl cell develop-
ment; whereas when IL-4 is not produced during priming,
activated CD4+ T cells maintain expression of the IL-
1ZRPZ chain, allowing Thl cell maturation independently
of IFN-y. The importance of IFN-y in favoring the Thl
response during infection with L. mtGor_ has also been
debated. C57BL/h mice that are deficient in IFN-y devel-
op a Th2 response after L. fnajor infection [3]. In contrast,
SvlZY mice rendered genetically deficient for the binding
chain of the IFN-y receptor develop a Thl response [4].
Inasmuch as IFN-yR-I- mice on a 129/Sv/Ev background,
in contrast to IFN-y-knockout mice on a C57BL/6 back-
ground, do not produce an early IL-4 burst following infec-
‘tion with L. mtiol- (P Launois, JA Louis, unpublished
results), it is possible, in light of the discussion above, that
their CD4+ T cells do not require IFN-y signaling for
maintenance of IL-12RpZ chain expression and IL-12 sig-
naling if/ zVc0.
Finally, it is important to emphasize that resistance and/or
susceptibility to infection with L. mujor appear to be con-
trolled by several genes and thus probably involve several
mechanisms. [Jsing resistant BlO.DZ mice backcrnssed
into susceptible BALB/c mice, six loci located on chromo-
somes 6,7,10,11,15 and 16 were associated with resistance
to L. major infection, but none of them has a major effect
by itself [66”]. Another study using (BALB/c x
C57BL/6)F2 mice also showed a linkage to the HZ region
on the chromosome 17 and to chromosome 9 [67].
Conclusions The murine mode1 of infection with L.. rntior has not
only permitted validation of the two pathways of CD4+
T cell differentiation in eieo but also enabled decipher-
ing of the critical role of CD4+ T cell subsets in the out-
come of infection with an intracellular pathogen. This
mode1 has already been invaluable in recent years for
identifying some molecular mechanisms operating in
viuo in the differentiation of CD4+ T cell subsets in the
periphery. A better definition of these mechanisms is a
prerequesite for the rational development of efficient
immunoprophylactic and immunotherapeutic measures
applicable to humans. Information gained by studying
this disease, which afflicts mainly the developing world,
has no doubt significantly added to our understanding of
critical issues related to the T cell response. It is impor-
tant that this knowledge foments the development of
novel strategies to prevent and treat this and other seri-
ous infectious diseases.
1.
2.
3.
4.
5.
6.
7. .
Acknowledgements &rk from the authors’ laboratory i\ supported by the SHiss National Science Foundation, the European Ilnion and thr \\idd Health Organisation. P Launoi~ is on leave from rhtt Pasteur Inscitut~. Paris.
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l of special interest l * of outstanding interest
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