Damage signals preferentially activate killer CD8+/- regulatory T cells to protect injured tissue

Josyula, A.; Fertil, D.; Hartigan, D. R.; Rudy, P.; Sharma, S.; Fashina, T.; Maclean, E.; Coogan, A. B.; Ngo, T. B.; Sundaresan, V.; Sadtler, K.

doi:10.1101/2025.01.13.632166

bioRxiv · 10.1101/2025.01.13.632166

Damage signals preferentially activate killer CD8+/- regulatory T cells to protect injured tissue

Josyula, A.·Fertil, D.·Hartigan, D. R.·Rudy, P.·Sharma, S.·Fashina, T.·Maclean, E.·Coogan, A. B.·Ngo, T. B.·Sundaresan, V.·Sadtler, K.

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Abstract

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+ naive T cell retention and B cell recruitment to injured muscle. These naive 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 naive 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.

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Josyula, A., Fertil, D., Hartigan, D. R., Rudy, P., Sharma, S., Fashina, T., Maclean, E., Coogan, A. B., Ngo, T. B., Sundaresan, V., Sadtler, K.. 2025-01-14. Damage signals preferentially activate killer CD8+/- regulatory T cells to protect injured tissue. https://doi.org/10.1101/2025.01.13.632166

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