Immune Regulation during Experimental Visceral Leishmaniasis

Abstract

Visceral Leishmaniasis (VL) is a chronic infectious disease caused by the protozoan parasites Leishmania donovani and L. infantum (chagasi) responsible for significant morbidity and mortality in the developing world. Transmitted by sand fly vectors, Leishmania parasites preferentially infect host macrophages throughout the viscera. Experimental L. donovani infection in genetically susceptible mice elicits a highly organ-specific outcome that mirrors much of the immunopathology observed in human VL patients. In this context, the liver is a site of an acute, resolving infection whereas parasite persistence is established in the chronically infected spleen. Generation of an effective immune response against infection requires IFNγ- and TNF-producing CD4+ T(h1) cells. Functional impairment of this pro-inflammatory subset is noted during chronic infection. Here, we describe 3 distinct pathways by which L. donovani promotes persistence within the host via the impairment of protective Th1 responses. IL-10 is a potent immunoregulatory cytokine well known for its T cell-modulatory activity. IL-10-producing CD4+ Th1 (Tr1) cells were found to contribute to much of the dysregulation observed during chronic L. donovani infection in C57BL/6 mice. While not influencing parasite control, Foxp3+ regulatory T(reg) cells were determined to be required for the induction of Tr1 cell populations during established infection. During chronic infection, however, Treg cells appeared to restrict the expansion of pathogenic Tr1 cells.