A T cell extrinsic mechanism by which IL-2 dampens Th17 differentiation

•Variants in il2 are genetically linked to autoimmune susceptibility.•High IL-2 phenotypes are associated with resistance.•Activated tissue resident macrophages can sense IL-2.•IL-2 induces IFN-g and IL-27 in macrophages to dampen pathogenic Th17 differentiation.•IL-2 can act T cell extrinsically to influence autoimmune susceptibility.

Genetic variants in il2 and il2ra have been associated with autoimmune disease susceptibility in both genome-wide association studies (GWAS) in humans and in genetic linkage studies in experimental models of autoimmunity. Specifically, genetic variants resulting in a low IL-2 phenotype are susceptibility alleles while variants resulting in a high IL-2 phenotype are resistance alleles. The association of high IL-2 phenotypes with resistance has been attributed primarily to the T cell intrinsic promotion of regulatory T cell development, maintenance, and function; however, IL-2 can also act T cell intrinsically to dampen differentiation of pathogenic IL-17-producing Th17 cells. Here, we have uncovered a novel T cell extrinsic mechanism whereby IL-2 promotes both IFN-γ and IL-27 production from tissue resident macrophages which in turn dampen the differentiation of pathogenic Th17 cells.