Hepatic Stellate Cells Regulate Liver Immunity to Visceral Leishmaniasis Through P110δ-Dependent Induction and Expansion of Regulatory T Cells in Mice

Visceral leishmaniasis (VL) is associated with severe immune dysfunction and if untreated leads to death. Because the liver is one of the primary target organs in VL, unraveling the mechanisms governing the local hepatic immune response is important for understanding the immunopathogenesis of VL. We previously reported that mice with inactivating knockin mutation in the p110 delta gene (p110 delta(D910A)) are resistant to VL, due in part to impaired regulatory T-cell (Treg) expansion. In this study, we investigated the mechanism of this resistance by focusing on hepatic stellate cells (HSCs), which are known to regulate Treg induction and expansion. We show that HSCs are infected with Leishmania donovani in vivo and in vitro and that this infection leads to the production of interleukin-2, interleukin-6, and transforming growth factor-beta, cytokines known to induce Tregs. We further demonstrate that L. donovani infection leads to expansion of HSCs in a p110 delta-dependent manner and that this correlated with proliferation of hepatic Tregs in vivo. In vitro studies clearly show that L. donovani-infected HSCs induce CD4(+) T cells to become Tregs and expand Tregs in a p110 delta-dependent manner. Targeted depletion of HSCs during infection caused a dramatic reduction in liver Treg numbers and proliferation, which was associated with a decrease in interleukin-10 production by hepatic T cells and a more efficient parasite control. Conclusion: These results demonstrate the critical role of HSCs in the pathogenesis of VL and suggest that the enhanced resistance of p110 delta(D910A) mice to L. donovani infection is due in part to impaired expansion and inability of their HSCs to induce and expand Tregs in the liver.