Distinct characteristics of hippocampal pathogenic TH17 cells in a mouse model of depression

Increasing evidence indicates that multiple actions of the immune system are closely intertwined with the development of depression and subsequent recovery processes. One of these interactions is substantial evidence that the T(H)17 subtype of CD4(+) T cells promotes susceptibility to depression-like behaviors in mice. Comparing subtypes of CD4(+) T cells, we found that administration of T(H)17 cells, but not T(H)1 cells or T-REGS, promoted susceptibility to learned-helplessness depressive-like behavior and accumulated in the hippocampus of learned helpless mice. Adoptively transferred T(H)17 cells into Rag2(-/-) mice that are devoid of endogenous T cells increased susceptibility to learned helplessness, demonstrating that increased peripheral T(H)17 cells are capable of modulating depression-like behavior. Moreover, in wild-type mice, adoptively transferred T(H)17 cells accumulated in the hippocampus of learned-helpless mice and induced endogenous T(H)17 cell differentiation. Hippocampal T(H)17 cells from learned-helpless mice expressed markers of pathogenic M17 cells (CCR6, IL-23R) and of follicular cells (CXCR5, PD-1), indicating that the hippocampal cells are T-FH-17-like cells. Knockout of CCR6 blocked T(H)17 cells from promoting learned helplessness, which was associated with increased expression of PD-1 in CCR6-deficient T(H)17 cells. In summary, these results reinforce the conclusion that depression-like behaviors are selectively facilitated by T(H)17 cells, and revealed that these cells in the hippocampus of learned helpless mice display characteristics of T-FH-like cells, which may contribute to their pathogenic actions in promoting depression.