CD4+ T cells in the pathogenesis of visceral leishmaniasis

Visceral leishmaniasis, caused by infection with the intracellular protozoan Leishmania donovani, is a chronic disease that affects the spleen, liver and bone marrow. Patients present with high parasite burdens in visceral organs, splenomegaly, cachexia, pancytopenia and will progress to death if not treated. Control of Leishmania infection is dependent on Th1 (IFNγ producing) CD4+ T cells, which activate macrophages to produce nitric oxide and kill the intracellular parasites. Despite there being an expansion of CD4+ T cells and an increase in pro-inflammatory molecules in the spleen, humans with active visceral leishmaniasis cannot control infection. We have established an experimental model of chronic progressive visceral leishmaniasis in hamsters, which mimics clinical features seen in humans, to determine the mechanisms of disease. The studies presented here focus on the role splenic CD4+ T cells play during chronic visceral leishmaniasis. A global view of the hamster splenic transcriptome during chronic infection provided insights into potential genes involved in disease pathogenesis. The characterization of the responding CD4+ T cells in chronic progressive visceral leishmaniasis in hamsters is described here as a mixed Th1 and Th2 response marked by increased mRNA of associated transcription factors, cytokines and chemokines. The capacity for the CD4+ T cells from the chronically infected hamsters to activate macrophages and induce parasite killing was present but marginally effective. Increased markers of T cell exhaustion in total spleen tissue led to the exploration of this as a potential contributor to suboptimal T cell effector function. We discovered that the splenic CD4+ T cell and macrophage populations expressed inhibitory receptors and ligands, respectively. Blocking PD-L2 led to a significant decrease in parasite burden revealing a pathogenic role for the PD-1 pathway in chronic visceral leishmaniasis. Inhibitory molecules are possible targets for immunotherapeutics or combinatory treatment regimens for chronic visceral leishmaniasis. Further studies into the role of PD-1 expression in CD4+ T cells during disease will provide better understanding of the mechanisms involved in immunopathogenesis of chronic visceral leishmaniasis.