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 (Batf3 ^-/-) mirror those of autoimmune mice (Aire ^-/-). Mechanistically, we determined that cDC1s prime killer regulatory T cells (CD8^+/-Ly49⁺Tregs) 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 CD62L⁺CCR7⁺ 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 CD8^+/-Ly49⁺ Tregs. Furthermore, clinically used materials that promote wound healing enrich CD8^+/-Ly49⁺ Treg function whereas those that are associated with pathology promote naïve T cell and B cell accumulation. We hypothesize that CD8^+/-Ly49⁺ Tregs maintain self-tolerance after tissue damage and avert autoimmunity by eliminating naive T cells and preventing pathogenic B cell activation.