Spinal cord injury (SCI) increasingly affects aged individuals, where functional impairment and mortality are highest. However, the aging-dependent mechanisms underpinning tissue damage remain elusive. Here, we find that natural killer-like T (NKLT) cells seed the intact aged human and murine spinal cord and multiply further after injury. NKLT cells accumulate in the spinal cord via C-X-C motif chemokine receptor 6 and ligand 16 signaling to clonally expand by engaging with major histocompatibility complex (MHC)-I-expressing myeloid cells. NKLT cells expressing natural killer cell granule protein 7 (Nkg7) disrupt myeloid-cell-dependent wound healing in the aged injured cord. Nkg7 deletion in mice curbs NKLT cell degranulation to normalize the myeloid cell phenotype, thus promoting tissue repair and axonal integrity. Monoclonal antibodies neutralizing CD8+ T cells after SCI enhance neurological recovery by promoting wound healing. Our results unveil a reversible role for NKG7+CD8+ NKLT cells in exacerbating tissue damage, suggesting a clinically relevant treatment for SCI.

Clonally expanded, targetable, natural killer-like NKG7 T cells seed the aged spinal cord to disrupt myeloid-dependent wound healing