Circulating memory-phenotype CD4+ T cells rapidly accumulate in the ischemic gut to exacerbate tissue injury in an innate manner.

Memory-phenotype (MP) CD4+ T lymphocytes develop from peripheral naive precursors via self-recognition at homeostasis. While MP cells exert innate immune function in infectious and autoimmune contexts, their functional significance in ischemia-reperfusion injury (IRI) remains unclear. Here we show that blood-circulating MP lymphocytes rapidly infiltrate the gut in the absence of antigen recognition during intestinal IRI. This MP migration is directed by α4β7 that binds to vascular MAdCAM-1, with the latter's expression immediately upregulated by IRI-induced TNF-α. Once accumulated in the gut, MP cells respond to IL-12 to produce IFN-γ that elevates CXCL1 and CXCL2 levels and orchestrates neutrophils, thereby exaggerating tissue injury. Furthermore, such innate MP responses are operative in hepatic but not renal IRI. Together, our results reveal blood-circulating MP cells as a unique innate amplifier of IRI that rapidly accumulates in the gut to exacerbate tissue injury via neutrophil orchestration.