Abstract
Depression is prevalent and debilitating and has been linked to inflammation. Inflammation is associated with increases in CD4 cells that produce IL-17A (Th17 cells) that promote depression in mice. We examined the mechanisms by which Th17 cells promote depressive-like behaviors. Th17 cells, but not Th1 cells, promoted depressive-like behaviors, and Th17 cells accumulated in the prefrontal cortex and hippocampus, but not in cerebellum, of mice exhibiting stress-induced learned helplessness depressive-like behavior. Adoptive transfer of Th17 cells into Rag2−/− mice, which are devoid of endogenous T cells, was sufficient to promote susceptibility to learned helplessness, demonstrating that increased peripheral Th17 cells can affect behavior. Moreover, adoptively transferred Th17 cells accumulated in the hippocampus of learned helpless mice, and induced endogenous Th17 cell differentiation. Characterization of hippocampal Th17 cells in learned helpless mice revealed that the Th17 cells express CCR6 and IL-23R, which have previously been shown to be markers of pathogenic Th17 cells, and CXCR5, a marker of follicular T cells. CCR6, but not CXCR5, was required to promote Th17 cell-dependent depressive-like behavior. PD-1 expression on Th17 cells was increased in the mice that received CCR6 deficient Th17 cells, providing a possible link between T follicular cells expressing PD-1 and pathogenic CCR6 expressing Th17 cells in the brain. In conclusion, Th17 cells and associated pathways may be novel molecular targets for depression.
