Dendritic cell regulation of immunity to Leishmania donovani

Dendritic cells lie at the interface of innate and adaptive immunity, critically contributing to the generation of an antigen-specific immune response. Although the mechanisms by which they initiate protective immunity are well characterised, their precise contribution to the subsequent regulation of immunity, particularly in the context of chronic infection, is less fully described. Leishmania donovani is an intracellular protozoan parasite of mammalian phagocytes, capable of establishing a persistent and life-threatening infection in man. Associated with profound immunopathology and chronic immune suppression, visceral leishmaniasis is endemic to some of the world’s most resource-poor regions. There is no vaccine and current therapeutic options are limited by parasite resistance, high toxicity and prohibitive costs. As such, a deeper understanding of the immunological mechanisms underlying this disease is critical for the development of effective novel interventions. Phenotypic and functional analysis of CD11chi conventional dendritic cell subsets (cDCs) revealed widespread alterations as a result of chronic infection in the murine spleen. cDCs displayed a limited capacity for costimulatory molecule expression and pro-inflammatory cytokine production ex vivo. Instead, the preferential production of the immunoregulatory cytokines IL-10 and IL-27 led to the establishment of an auto- regulatory cytokine cascade, modulating cDC function and limiting their capacity to direct effector T cell polarisation in vitro. 2 Conditional in vivo ablation of CD11c+ cells during chronic infection suggested a key role for DCs in the maintenance of pathology and parasite persistence in the spleen, whilst adoptive transfer approaches revealed for the first time that IL-10+IL-27+ cDCs facilitated the expansion of IL-10 producing Th1 cells in vivo and significantly contributed to the progression of disease. Taken together, this study reveals a paradoxical capacity for cDCs to suppress effective immune responses during chronic parasitic infection and highlights novel immunoregulatory mechanisms associated with this neglected tropical disease.