Chronic stress promotes sex-divergent Type 1, 2 and 17 responses in brain resident lymphocytes.

Abstract

T helper cytokines such as IFN{gamma} and IL-17 are dysregulated in a subset of patients with depression and are associated with poor responses to treatment. Both IFN{gamma} and IL-17 have been shown to regulate neural circuits involved in behavioral changes implicated in depression. However, the cellular source and the regulatory mechanisms governing these cytokines in this context remain incompletely understood. We analyzed brain lymphocytes in response to unpredictable chronic mild stress (UCMS), a model of depression with strong face and construct validity. We confirmed that UCMS induced depressive-like behavior in both male and female mice. Interestingly, UCMS preferentially reduced regional synaptic density in female and neuron counts in male hippocampi. Using single cell RNAseq, we identified T helper cytokine signatures to be enriched in distinct lymphocyte lineages expressing tissue resident markers and are regulated by both sex and chronic stress. Female brain-resident {gamma}{delta}T cells are significantly enriched for type 2 and type 17 signatures and have higher expression of inflammasome genes such as Nlrp3 and Il1b whereas male {beta}T cells and NKT cells are enriched for type 1 signatures and have elevated Cxcr3 and Il27ra expression. Chronic stress amplified the sex differences and preferentially increased the type 1 response including IFN{gamma} production in males at both the transcriptome and protein level. Type 17 response (e.g. IL-17A and IL-17F production) is also increased in response to UCMS, however with sex-divergent polarization: IL-22 is decreased in female and increased in male brain lymphocytes. Mechanistically, we found that UCMS suppressed P4ha1 in male and Zfp36 in female brain tissue resident lymphocytes. P4HA1 was previously shown to restrict mitochondrial function and limit type 1 responses in CD8 T cells, whereas ZFP36 is a suppressor of inflammatory cytokine translation. Consistent with this finding, ex vivo CD3-dependent stimulation of brain immune cells showed stress-dependent increase in cytokine production with sex-specific effects. Our study provides the cellular and molecular framework for chronic stress-induced tissue resident lymphocyte dysregulation and its sex bias in the brain, with implications for depressive disorders marked by inflammation.