CD4+ T cell dysfunction during visceral leishmaniasis

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PROJECT SUMMARY/ABSTRACT Visceral leishmaniasis is a devastating, neglected tropical disease, ultimately leading to multiorgan failure and death when left untreated. As with many parasitic infections, efforts to develop an effective vaccine have remained unsuccessful. In contrast to a number of infectious pathogens which can be controlled by neutralizing antibodies and/or cytotoxic CD8+ T cells, protection against leishmaniasis is largely mediated by T helper 1 differentiated CD4+ T cells, but how CD4+ T cell activation, differentiation, and function are regulated during visceral leishmaniasis is still largely unknown. A major limitation to these studies has been the inability to accurately identify Leishmania-specific CD4+ T cells in experimental model systems in order to assess T cell longevity and functions during and after the course of the infection. Here, using a recently identified MHC-II epitope conserved across Leishmania species, we show that in contrast to cutaneous versions of leishmaniasis, antigen-specific CD4+ T cells become functionally exhausted during visceral leishmaniasis, produce IL-10, and express high levels of the inhibitory receptors PD-1 and CTLA-4. This suggests that rather than remaining “hidden”, high parasite burden and/or antigen load overwhelms the adaptive immune system to the point where antigen-specific CD4+ T cells lose the capacity to produce the necessary pro-inflammatory cytokines to kill parasites residing within macrophages. Because there is currently no effective vaccine and limited treatment options for leishmaniasis, we have generated recombinant Vaccinia virus (VacV) vectors expressing the immunodominant Leishmania epitope targeted for MHC-II presentation to study the CD4+ T cell response against this parasitic infection. To begin to investigate the mechanisms of CD4+ T cell activation and to identify strategies to reverse or limit T cell dysfunction during visceral leishmaniasis, we will 1) define the functions and gene expression profiles of antigen-specific CD4+ T cells that become activated following either cutaneous or visceral Leishmania infections and 2) determine if therapeutic viral immunization combined with immunotherapy restores function to CD4+ T cells during visceral leishmaniasis. The overall goal of this project will be to begin to define the mechanisms that regulate CD4+ T cell function and dysfunction during visceral leishmaniasis, which will contribute to our long-term goal of improving vaccine design and therapies against this complex parasite.