Abstract
Immunosuppression is a characteristic feature of chronic leishmaniasis. The dynamicity and the functional cross talks of host immune responses during Leishmania infection are still not clearly understood. Here we explored the functional aspects of accumulation of immune suppressive cellular and cytokine milieu during the progression of murine visceral leishmaniasis. In addition to IL-10 and TGF-β, investigation on the responses of different subunit chains of IL-12 family revealed a progressive elevation of EBI-3 and p35 chains of IL-35 with Leishmania donovani infection in BALB/c mice. The expansion of CD25 and FoxP3 positive T cells is associated with loss of IFN-γ and TNF-α response in advanced disease. Ex-vivo and in vivo neutralization of TGF-β and EBI-3 suggests a synergism in suppression of host anti-leishmanial immunity. The down-regulation of EBI-3 and TGF-β is crucial for re-activation of JAK-STAT pathway for induction as well as restoration of protective immunity against L. donovani infection.
Highlights
Maintenance of immunological self-tolerance and homeostasis by restraining disproportionate and detrimental immune responses is primarily mediated by regulatory cytokine secreting lymphocytes [1]
We show the dynamicity of different subsets of CD4+ T cells at different stages of L. donovani infection of BALB/c mice and their contribution to different cytokine responses
In consistence to the previous reports of IL-10 and TGF-β, we report the effect of the subunit chains of IL-35
Summary
Maintenance of immunological self-tolerance and homeostasis by restraining disproportionate and detrimental immune responses is primarily mediated by regulatory cytokine secreting lymphocytes [1]. The correlation between effector and regulatory cell populations especially in terms of sensing and secretion of cytokines during diseased condition is still not well understood [6]. Several studies have suggested the role of IL-10 and TGF-β in subversion of proinflammatory response in active VL [10, 11]. Apart from IL-10 and TGF-β, the role of other immunosuppressive cytokines in VL is yet to be established. IL-35 is a heterodimeric cytokine with two polypeptides “α” and “β” chains. These polypeptides may participate in the construction of two or more cytokines for
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