Th17 cells confer both systemic and mucosal protection against Trypanosoma cruzi infection

Abstract

Abstract Chagas disease is caused by chronic infection with the Trypanosoma cruzi parasite. It affects 11 million people, a third of whom will develop life-threatening cardiac and gastrointestinal morbidities. Optimal immunity to this intracellular pathogen requires CD8+ and CD4+ T cell responses. Recently, we demonstrated that CD4+ Th17 cells can confer even stronger protection against T. cruzi infection than CD4+ Th1 cells, typically considered most important for intracellular immunity. To study systemic protection, we adoptively transferred RAG KO mice with naive polyclonal CD8+ T cells and parasite-specific Th1 or Th17 cells, then infected them subcutaneously. Th17 cell co-transfer resulted in 100% long-term survival, compared to 38% with Th1 co-transfer. Mechanistically, the Th17 cells produced high levels of IL-21, which provided help for the activation of CD8+ T cells. Th17 cells given with IL-21R KO CD8+ T cells failed to protect mice, underscoring the importance of IL-21 signaling. Although CD8+ T cells were required for systemic immunity, Th17 cells alone protected against mucosal infections. Mice reconstituted with Th17 cells prior to orogastric challenge had decreased parasite burdens in the stomach and lower levels of dissemination to other organs, indicating a direct protective effect. In vitro, we discovered that Th17 cells can directly suppress infection in macrophages via the IL-17A-dependent triggering of NADPH oxidase, important for the phagocyte respiratory burst response. In summary, we have shown that Th17 cells drive robust systemic and mucosal immune responses against an intracellular parasite through both direct and indirect means, highlighting important new roles for Th17 cells in intracellular immunity.