Perforin Generated by CD8+ T Cells Exacerbates IBD-Induced Depression by Promoting CXCL9 Production in Intestinal Epithelial Cells

Abstract

Background & Aims

Approximately 25.2% of inflammatory bowel disease (IBD) patients suffer from psychological disorders, particularly depression. Recent studies have indicated a close relationship between intestinal immunity and brain disorders.

Methods

We performed transcriptome analysis and immunofluorescence staining of colonic samples from IBD patients. The role of perforin generated by colonic CD8⁺ T cells in IBD-induced depression was investigated in DSS- and CD8⁺ T-cell transfer-induced colitis by using Prf1-EGFP reporter and Prf1 knockout mice.

Results

In this study, we revealed a significant correlation between depressive symptom severity and perforin production in CD8⁺ T cells in both IBD patients and mice with colitis. Moreover, perforin deficiency in CD8⁺ T cells mitigated both inflammation and depressive-like behaviors in mice with colitis. Mechanistically, perforin and granzyme B were found to stimulate the expression of CXCL9 in colonic epithelial cells. CXCL9 was shown to be released into the circulation and to enter the hippocampus, where it induced endoplasmic reticulum (ER) stress in hippocampal neurons through the CXCR3-HSPA5 axis. This cascade of events subsequently was found to exacerbate depression. Neutralizing CXCL9 in vivo alleviated depression but had no effect on colitis in mice.

Conclusions

Perforin generated by colonic CD8⁺ T cells promotes intestinal epithelial cell CXCL9 production, which leads to neuronal ER stress in hippocampus and induces depression in IBD.