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

TL;DR

Stem-like memory CD8+ T cells migrate to the gut, reducing a brain-boosting chemical and increasing depression risk.

Contribution

Identifies a novel immune-gut-brain axis involving CD8+ TSCM cells and gut microbiome metabolism in depression.

Findings

CD8+ TSCM cells migrate to the intestine via the PPBP–CXCR2 axis in stress-susceptible models.

These cells reduce tyrosine-metabolizing bacteria, lowering homovanillic acid and causing neuroinflammation.

Adoptive transfer of CD8+ TSCM cells induces depressive-like behavior without brain infiltration.

Abstract

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 (TSCM) cells, is elevated in patients and stress-susceptible mice. CD8+ TSCM cells from patients display unique transcriptional programs and correlated with depression severity. Adoptive transfer of stress-derived CD8⁺ TSCM cells induced depressive-like behavior and neuroinflammation in recipients, without brain migration. Employing a whole-body immunolabeling technology, we discover CD8+ TSCM cells migrated to intestine via the interaction of pro-platelet basic protein and C-X-C motif chemokine receptor 2. CD8+ TSCM 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+ TSCM cells and gut microbial metabolism, shedding light on potential mechanisms underlying depression and suggesting avenues for therapeutic intervention.

Major depressive disorder has been linked to peripheral immune dysfunction. Here, the authors identify elevated stem cell-like memory CD8⁺ T cells in patients and in a murine stress model show migration to the intestine via PPBP-CXCR2 and suggest gut CD8 cells modulate tyrosine metabolizing bacteria and homovanillic acid potentiating neuroinflammation and depressive phenotype.

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