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T cell expression of caspase‐8 inhibitor vFLIP provides a Th1 cytokine environment, along with a protective Th2 response that increases immunity to Leishmania majorinfection. We investigated how apoptosis pathways mediated by death receptors and caspase‐8 affect cytokine responses and immunity to Leishmania majorparasites. Splenic CD4 T cells undergo activation‐induced apoptosis, and blockade of FasL‐Fas interaction increased IFN‐γ and IL‐4 cytokine responses to L. majorantigens. To block death receptor‐induced death, we used mice expressing a T cell‐restricted transgene for vFLIP. Inhibition of caspase‐8 activation in vFLIP mice enhanced Th1 and Th2 cytokine responses to L. majorinfection, even in the Th1‐prone B6 background. We also observed increased NO production by splenocytes from vFLIP mice upon T cell activation. Despite an exacerbated Th2 response, vFLIP mice controlled better L. majorinfection, with reduced lesions and lower parasite loads compared with WT mice. Moreover, injection of anti‐IL‐4 mAb in infected vFLIP mice disrupted control of parasite infection. Therefore, blockade of caspase‐8 activity in T cells improves immunity to L. majorinfection by promoting increased Th1 and Th2 responses.

Infection with Leishmania majorelicits myeloid‐derived suppressor cells, which kill Leishmania parasites despite suppressed T‐cell proliferation. Th1/Th2 cytokines play a key role in immune responses to Leishmania majorby controlling macrophage activation for NO production and parasite killing. MDSCs, including myeloid precursors and immature monocytes, produce NO and suppress T cell responses in tumor immunity. We hypothesized that NO‐producing MDSCs could help immunity to L. majorinfection. Gr1hi(Ly6Chi) CD11bhiMDSCs elicited by L. majorinfection suppressed polyclonal and antigen‐specific T cell proliferation. Moreover, L. major‐induced MDSCs killed intracellular parasites in a NO‐dependent manner and reduced parasite burden in vivo. By contrast, treatment with ATRA, which induces MDSCs to differentiate into macrophages, increased development of lesions, parasite load, and T cell proliferation in draining LNs. Altogether, these results indicate that NO‐producing MDSCs help protective immunity to L. majorinfection, despite suppressed T cell proliferation.