Neuroprotection against ischemic stroke requires a specific class of early responder T cells in mice

Immunomodulation holds therapeutic promise against brain injuries, but leveraging this approach requires a precise understanding of mechanisms. We report that CD8(+)CD122(+)CD49d(lo) T regulatory-like cells (CD8(+) TRLs) are among the earliest lymphocytes to infiltrate mouse brains after ischemic stroke and temper inflammation; they also confer neuroprotection. TRL depletion worsened stroke outcomes, an effect reversed by CD8(+) TRL reconstitution. The CXCR3/CXCL10 axis served as the brain-homing mechanism for CD8(+) TRLs. Upon brain entry, CD8(+) TRLs were reprogrammed to upregulate leukemia inhibitory factor (LIF) receptor, epidermal growth factor–like transforming growth factor (ETGF), and interleukin 10 (IL-10). LIF/LIF receptor interactions induced ETGF and IL-10 production in CD8(+) TRLs. While IL-10 induction was important for the antiinflammatory effects of CD8(+) TRLs, ETGF provided direct neuroprotection. Poststroke intravenous transfer of CD8(+) TRLs reduced infarction, promoting long-term neurological recovery in young males or aged mice of both sexes. Thus, these unique CD8(+) TRLs serve as early responders to rally defenses against stroke, offering fresh perspectives for clinical translation.