Migration of CD8 + TSCM cells into intestine via PPBP–CXCR2 axis increases host stress susceptibility by inhibiting gut microbiome-derived homovanillic acid

Psychosocial stress impacts immune system and brain function, yet mechanisms linking peripheral immune dysregulation to major depressive disorder remain unclear. Here, we demonstrate that a specific subset of T cells, the stem cell-like memory CD8⁺ T (T_SCM) cells, is elevated in patients and stress-susceptible mice. CD8⁺ T_SCM cells from patients display unique transcriptional programs and correlated with depression severity. Adoptive transfer of stress-derived CD8⁺ T_SCM cells induced depressive-like behavior and neuroinflammation in recipients, without brain migration. Employing a whole-body immunolabeling technology, we discover CD8⁺ T_SCM cells migrated to intestine via the interaction of pro-platelet basic protein and C-X-C motif chemokine receptor 2. CD8⁺ T_SCM cells decrease the abundance of tyrosine-metabolizing bacteria to reducing homovanillic acid production, triggered neuroinflammation and depressive symptoms. Thus, our findings uncover a complex interplay between CD8⁺ T_SCM cells and gut microbial metabolism, shedding light on potential mechanisms underlying depression and suggesting avenues for therapeutic intervention.