Multifaceted mechanisms of unconventional T cells in ischemia-reperfusion injury

Ischemia-reperfusion injury (IRI) constitutes a common pathological basis for organ dysfunction across various critical clinical conditions, including ischemic stroke, myocardial infarction, and organ transplantation. This review focuses on the functions of unconventional T cells in IRI in the brain, liver, kidneys, heart, and mucosal barrier organs, highlighting their diverse regulatory mechanisms in various tissue injury patterns. It also examines the dual functions of these cells in IRI: instead of solely acting as consistent pro-inflammatory effectors, they demonstrate a context-dependent immunomodulatory profile influenced by the organ microenvironment and disease stage, capable of promoting inflammatory damage and facilitating anti-inflammatory repair. Their behavior is shaped by a common injury response program that integrates local antigen cues, the cytokine milieu, metabolic checkpoints, and signals from the repair stage. Expounding on the spatiotemporal heterogeneity, functional plasticity, and regulatory networks of unconventional T cells in IRI will enhance our understanding of the immunopathological mechanisms. It also offers a theoretical basis and potential targets for formulating precision immunomodulatory strategies tailored to specific time windows and cell subsets.