Circulating memory-phenotype CD4+ T cells rapidly accumulate in ischemic organs to exacerbate tissue injury in an innate manner 2395

Description CD4+ T lymphocytes play an essential role in adaptive immunity. Within this population, we reported “memory-phenotype” (MP) cells that spontaneously arise from peripheral naïve precursors via self recognition in steady state. While previous studies revealed their innate function in lymphoid tissues, it remains to be determined whether blood-circulating MP cells have innate activities, and if so, what mechanisms dictate their activation and migration to extra-lymphoid organs. Ischemia-reperfusion injury (IRI) is induced by acute occlusion of organ-feeding arteries and subsequent reperfusion where innate immunity plays an important role. Using this model, here we demonstrate that circulating MP CD4+ T lymphocytes rapidly infiltrate to the intestinal lamina propria in the absence of antigen recognition during intestinal IRI. This MP cell migration is directed by ligation of α4β7 on MP cells to vascular MAdCAM-1, with the latter expression immediately induced by TNF-α upon reperfusion. Moreover, we show that upon accumulation in the gut, MP cells rapidly produce IFN-γ in response to IL-12 in an innate manner to orchestrate neutrophils, thereby exacerbating the tissue injury. Furthermore, our data argue that such α4β7-mediated innate responses of MP cells can also contribute to hepatic IRI. Together these results reveal an essential innate function of circulating MP CD4+ T lymphocytes that rapidly accumulate in ischemic organs to critically contribute to pathogenesis of IRI.