Distinct characteristics of hippocampal pathogenic T_H17 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_H17 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_H17 cells, but not T_H1 cells or T_REGS, promoted susceptibility to learned-helplessness depressive-like behavior and accumulated in the hippocampus of learned helpless mice. Adoptively transferred T_H17 cells into Rag2^-/- mice that are devoid of endogenous T cells increased susceptibility to learned helplessness, demonstrating that increased peripheral T_H17 cells are capable of modulating depression-like behavior. Moreover, in wild-type mice, adoptively transferred T_H17 cells accumulated in the hippocampus of learned-helpless mice and induced endogenous T_H17 cell differentiation. Hippocampal T_H17 cells from learned-helpless mice expressed markers of pathogenic T_H17 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_H17 cells from promoting learned helplessness, which was associated with increased expression of PD-1 in CCR6-deficient T_H17 cells. In summary, these results reinforce the conclusion that depression-like behaviors are selectively facilitated by T_H17 cells, and revealed that these cells in the hippocampus of learned helpless mice display characteristics of T_FH17-like cells, which may contribute to their pathogenic actions in promoting depression.