Th17 cells enhance CD8 T cell cytotoxicity via IL-21 production in tumor vaccinated mice.

Abstract

Abstract A precise tug-of-war between regulatory T (Treg) cells and IL-17-producing (Th17) CD4 T cells ensures appropriate reactivity to pathogenic challenge. While an imbalance favoring Treg activity leads to suboptimal responses, overactive Th17 activity promotes autoimmunity. Both Th17 and Treg cells represent a significant proportion of the tumor infiltrating lymphocytes (TILs) in melanoma patients. In this disease context, Tregs suppress effector cells via numerous mechanisms. Productive immune responses are believed to result from passive escape from Treg suppression. We report an active role for Th17 cells in dampening Tregs to promote CD8 effector T cell activity. Using a melanoma mouse model, we found that elimination of IL-17-producing cells prevents vaccine-induced anti-melanoma immunity. Using RNA-Seq analysis, we identified a gene expression (GE) signature that implicates the IL-21/IL-21R axis in the ability of Th17 cells to inhibit Tregs and to induce a cytolytic GE signature in CD8 T cells. Similarly compromised vaccine-induced anti-melanoma responses in both IL-21R-deficient and Th17 diminished mice further support a critical role for Th17 cells and IL-21. Ectopic expression of IL-21 rescued compromised anti-tumor responses in Th17 diminished mice, suggesting that Th17-specific production of IL-21 induces effective CD8-mediated anti-tumor immunity. Single-cell RNA-seq analysis elucidated dynamic changes in both the identity and phenotype of diverse TILs populations in response to Th17 cells and IL-21 expression. Together, these data suggest that Th17-specific IL-21 production impedes Treg suppression, resulting in increased CD8 T cell effector function, and changes in TILs populations.