ARTICLE
Some aspects of the spectrum of pathological manifestations in humans infected
with various Leishmania species have been successfully reproduced in inbred
mice of different genetic backgrounds following infection with Leishmania
major. This murine model of infection has thus been extensively used
in attempts to correlate component(s) of the immune response associated
with either spontaneous resolution of lesions or progressive disease.
Mice from most inbred strains are resistant to infection by L. major.
In contrast, mice from BALB strains are unable to control infection and
develop progressive disease [1]. Resistance and susceptibility have been
correlated with the appearance of parasite-specific CD4+ Th1
or CD4+ Th2 cells, respectively. The dominant role of IFN-gamma
produced by CD4+ Th1 cells in resistance to L. major
has been demonstrated [2, 3]. In mice, the IFN-gamma produced by Th1 cells
renders macrophages, the host cells for Leishmania, parasiticidal through
the synthesis of the inducible nitric-oxide synthase leading to the production
of toxic nitrogen radicals [4]. Susceptibility to L. major is also
governed by Th2-derived cytokines with macrophage deactivating properties.
This murine model on infection with L. major is now considered
as a powerful system to study the cellular and molecular mechanisms underlying
genetically determined differences in the differentiation of CD4+
Th subsest in vivo. It has been demonstrated that Th1 and Th2 effector
cells derive from a common CD4+ T cell precursor [5] and several
stimuli have been reported to influence the pathway of maturation of CD4+
T cell precursors [6]. Among these, cytokines themselves critically regulate
this process [6, 7]. Using CD4+ T cells transgenic for a unique
TCR alpha/beta receptor, it was demonstrated that IL-12 and IL-4 are crucial
for Th1 or Th2 cell maturation, respectively [6].
Development of polarized Th1 responses in genetically
resistant mice
The importance of IL-12 for the establishment of Th1 cell responses
in resistant mice following infection with L. major has been shown
using either anti-IL-12 neutralizing antibodies or mice with disruption
of the IL-12 gene [8, 9]. Conversely, treatment of BALB/c mice with exogenous
recombinant IL-12 resulted in Th1 responses and resistance to L. major
in these otherwise susceptible mice [10, 11].
Development of polarized Th2 responses in genetically
susceptible BALB mice
Results obtained more than 10 years ago already supported a requisite
role for IL-4 in mediating both Th2 cell differentiation and susceptibility
to L. major in susceptible BALB/C mice [12]. In this context, we
have demonstrated a burst of IL-4 mRNA expression in the draining lymph
node CD4+ cells of BALB/c mice within 24 hours after infection
with L. major [13]. It is noteworthy that this IL-4 burst occurred
during the period when neutralizing IL-4 antibodies were capable of redirecting
protective Th1 maturation in BALB/c mice [12, 14]. After this initial
IL-4 mRNA burst, IL-4 mRNA expression returned to base line values before
the occurrence of a second and permanent wave of IL-4 transcripts which
reflects the establishment of a Th2 response. The cognate recognition
of a single epitope of the Leishmania homolog of mammalian RACK1, designated
LACK [15] was demonstrated to drive this early IL-4 response by a restricted
population of MHC class II restricted CD4+ T cells that express
the Vbeta4-Valpha8 TCR chains [16].
The importance of these Vbeta4-Valpha8 CD4+ T cells in Th2
cell maturation following infection with L. major was demonstrated
using BALB/c mice deficient in Vbeta4+ cells following neonatal
exposure to MMTV (SIM), a mouse mammary tumor virus encoding a superantigen
leading to permanent deletion of Vbeta4+ cells. The early IL-4
mRNA burst after infection with L. major was absent in Vbeta4 CD4+
T cell-deficient BALB/c mice and Th2 cell development did not occur in
these mice which did not suffer progressive disease [16]. Similarly to
Vbeta4-deficient mice, BALB/c mice rendered tolerant to LACK as a result
of the transgenic expression of this molecule under MHC class II promoters
in the thymus were resistant to L. major and developed a Th1 response
[17]. In addition, the induction of a specific unresponsive state in LACK-reactive
Vbeta4-Valpha8 CD4+ T cells following treatment of BALB/c mice
with altered LACK proteins that differ by a single amino acid from the
natural I-Ad-restricted epitope antagonized early IL-4 response
to the wild type LACK epitope, inhibited Th2 cell development, redirected
Th1 cell maturation and resulted in long term protection [18]. Although
it has been suggested that these LACK-reactive Vbeta4-Valpha8 CD4+
T cells were activated before exposure to LACK [19], our recent data revealing
the functional plasticity of these cells in terms of cytokine production
rather suggest that they are not differentiated memory cells [20].
Analysis of the accessory cells requirement for the expression of IL-4
transcripts in Vbeta4-Valpha8 CD4+ T cells following infection
has further and unexpectedly demonstrated that B cells were essential
(manuscript in preparation). The hypothesis that simultaneous recognition
by T cells of their specific epitope on B and professional APC (i.e.
dendritic cells) could signal B cells to produce cytokine(s) able to interfere
with the Th1 inducing signals from DC in close vicinity is attractive
and currently being investigated.
The use of the murine model of infection with
L. major to reveal the opposite effects
that IL-4 can exert on Th development
In contrast to its well known role in Th2 cell maturation, several results
obtained with IL-4 transgenic and IL-4 deficient mice suggested that IL-4
may also promote Th1 cell development [21-25]. Studying the effects of
exogenous IL-4 during the initiation of CD4+ T cell responses
to OVA in vitro and to L. major in vivo we could
show recently that when present only during the initial period of activation
of dendritic cells (DCs), IL-4 instructed the differentiation of CD4+
T cells toward a Th1 phenotype and established resistance to L. major
even in susceptible BALB/c mice. In both systems, this effect of IL-4
on Th1 cell development was totally dependent upon DC-derived IL-12 which,
in turn, down-regulated early IL-4 production by LACK-specific Vbeta4Valpha8
CD4+ T cells in BALB/c mice [26]. In contrast, when also present
during the period of T cell priming, IL-4 induced Th2 cell maturation
and susceptibility to L. major, even in resistant Vbeta4+
cell-deficient BALB/c mice. Thus, since receptors for IL-4 and most other
cytokines are expressed by a variety of cells, it is likely that, beyond
cytokine concentration, the kinetics of cytokine action, including consecutive
or preferential interactions with distinct cell subtypes, significantly
contribute to their pleiotropic effects in vivo.
CONCLUSION
The murine model of infection with L. major has permitted us to
demonstrate in vivo the existence and the importance of distinct
CD4+ T cell subpopulation in vivo. This model is now
considered as a powerful tool to study the cellular and molecular mechanisms
operating in the selective development of peripheral CD4+ T
cells in vivo. Knowing these mechanisms is essential for the development
of novel interventional strategies for the prevention and treatment of
serious infectious diseases.
Acknowledgements
Our groups are supported by grants from the Swiss National Science Foundation,
the Deutsche Forschungsgemeinschaft and the French Ministry of Research.
Article accepted on 26/2/02
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