BACKGROUND & AIMS: Approximately 25.2% of patients with inflammatory bowel disease (IBD) 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 patients with IBD. The role of perforin generated by colonic CD8(+) T cells in IBD-induced depression was investigated in dextran sulfate sodium- 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 patients with IBD 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 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 endoplasmic reticulum stress in hippocampus and induces depression in IBD.