Th17 cells are more protective than Th1 cells against the intracellular parasite Trypanosoma cruzi.

Abstract

Abstract Th1 cells are considered the major CD4+T helper subset responsible for the control of intracellular pathogens, including Trypanosoma cruzi, the protozoan parasite of Chagas disease. Th17 cells are known for their involvement in autoimmunity and the defense against some extracellular organisms, but are generally not believed to have a significant function during intracellular infections. In contrast, we show that Th17 cells are highly protective against the intracellular pathogen T. cruzi. We reconstituted RAG KO mice lacking endogenous T cells with polyclonal CD8+ T cells and parasite-specific Th1 or Th17 cells, generated from novel T cell receptor transgenic mice recently developed by us. After adoptive cell transfer, recipients were infected with a normally lethal dose of T. cruzi. Th17 cells impressively protected 100% of mice from mortality long-term, while Th1 cells protected only 38%. Transfer of Th17 cells alone failed to protect, implicating helper effects on CD8+ T cells as the basic mechanism of Th17-mediated intracellular immunity. We confirmed this using in vitro assays, and discovered that Th17 cells help activate CD8+ T cells through IL-21 secretion, indicating a protective mechanism surprisingly independent of the main Th17 cytokine IL-17A. In vivo, co-transfer of IL-21R knock-out CD8+ T cells with Th17 cells failed to protect mice, confirming the importance of IL-21 signaling. In summary, our data define an important new role for Th17 cells in the defense against a major intracellular human pathogen and define novel mechanisms of Th17 cell effects. This work increases our understanding of the protective immune interactions in T. cruzi infection, and more broadly, illuminates the growing diversity of Th17 cell roles.