Damage signals preferentially activate killer CD8 regulatory T cells to protect injured tissue.

Self-antigens that are obscure to immune cells under homeostasis, are exposed following tissue damage and can trigger autoimmunity. Our previous work showed that conventional type 1 dendritic cells (cDC1s) mediate immunoregulation after traumatic skeletal muscle injury. Here, we found that, immune responses to injury in cDC1-depleted mice ( ) mirror those of autoimmune mice ( ). Mechanistically, we determined that cDC1s prime killer regulatory T cells (CD8Ly49Tregs) which express Ly49 inhibitory receptors and HELIOS. These killer-like Tregs are clonally diverse and carry T cell receptors associated with self-reactivity and response to hydrophobicity. cDC1 or CD8 deletion promoted CD62LCCR7 naïve T cell retention and B cell recruitment to injured muscle. These naïve T cells, which are implicated in autoimmunity, strongly correlate with B cell abundance in the muscle and are selectively pruned by CD8Ly49 Tregs. Furthermore, clinically used materials that promote wound healing enrich CD8Ly49 Treg function whereas those that are associated with pathology promote naïve T cell and B cell accumulation. We hypothesize that CD8Ly49 Tregs maintain self-tolerance after tissue damage and avert autoimmunity by eliminating naive T cells and preventing pathogenic B cell activation.