Role of CD40 in the regulation of regulatory T cells (T reg.) in Leishmaniasis

Abstract

Leishmania donovani, a protozoan parasite, inflicts the fatal disease visceral leishmaniasis, which is characterized by severe immunosuppression. Regulatory T cells (T-reg) mediate immunosuppression and disease progression whereas CD8+ T cells contribute to host protection. Both the disease-promoting and host-protective T cells require CD40-CD40-ligand interaction for their functions suggesting an unknown dual role for CD40 in anti-parasite immune responses. Using Leishmania donovani infection in susceptible BALB/c mice expressing different levels of CD40, we show that CD8+CD40+ T cells function as contra-t-reg cells. Multicolor fluorescence-activated cell sorting analyses, have characterized the target of these contra-t-reg cells. Intriguingly, CD40+CD8+ T cells executed CD40-dependent cytotoxicity against CD4+ T-reg cells. CD40 signaled through Ras, Phosphatidylinositol- 3 kinase (PI-3K) and protein kinase C (PKC) resulting in NF-κB-dependent induction of granzyme B and perforin, the mediators of the cytotoxic function of CD8+ T cells. Adoptive transfer of these cells reduced the Leishmania donovani infection in susceptible BALB/c mice in vivo and reduced Leishmania infection in macrophages in vitro. These CD8+ contra-T-reg cells were apoptosed by IL-10. Thus, CD8+CD40+ T cells function as contra-T-reg cells modulating the course of Leishmania donovani infection, defining a CD40-regulated T-reg/contra-T-reg cellmediated finer regulation of anti-leishmanial immune response.