P2X7R+CD8αβ+ T cells exacerbate postoperative ileus by inducing the loss of enterochromaffin cells.

Postoperative ileus (POI) is a common complication after abdominal surgery, driven by inflammation. This study investigated how extracellular-ATP (eATP) and intestinal CD8αβ+ intraepithelial lymphocytes (IELs) contribute to POI. Using an intestinal manipulation mouse model, we found that CD8αβ+ IELs were increased and activated during POI, producing elevated granzyme B. Depletion of these T cells or inhibition of granzyme B ameliorated gastrointestinal transit impairment. Damage-induced eATP promoted granzyme B production in CD8αβ+ IELs via P2X7R signaling. Mechanistically, granzyme B degraded the tight-junction protein ZO-1, leading to enterochromaffin cell loss, reduced serotonin levels, and subsequent motility dysfunction. These findings reveal a pathway in which eATP activates CD8αβ+ IELs through the P2X7 receptor to drive enterochromaffin cell loss via granzyme B-mediated tight-junction degradation, identifying potential therapeutic targets for POI.