Direct presentation of inflammation-associated self-antigens by thymic innate-like T cells induces elimination of autoreactive CD8+ thymocytes.

You Y, Dunst J, Ye K, Sandoz PA, Reinhardt A, Sandrock I, Comet NR, Sarkar RD, Yang E, Duprez E, Agudo J, Brown BD, Utz PJ, Kastenmüller W, Gerlach C, Prinz I, Önfelt B, Kreslavsky T

Nat. Immunol. 25 (8) 1367-1382 [2024-08-00; online 2024-07-11]

Upregulation of diverse self-antigens that constitute components of the inflammatory response overlaps spatially and temporally with the emergence of pathogen-derived foreign antigens. Therefore, discrimination between these inflammation-associated self-antigens and pathogen-derived molecules represents a unique challenge for the adaptive immune system. Here, we demonstrate that CD8+ T cell tolerance to T cell-derived inflammation-associated self-antigens is efficiently induced in the thymus and supported by redundancy in cell types expressing these molecules. In addition to thymic epithelial cells, this included thymic eosinophils and innate-like T cells, a population that expressed molecules characteristic for all major activated T cell subsets. We show that direct T cell-to-T cell antigen presentation by minute numbers of innate-like T cells was sufficient to eliminate autoreactive CD8+ thymocytes. Tolerance to such effector molecules was of critical importance, as its breach caused by decreased thymic abundance of a single model inflammation-associated self-antigen resulted in autoimmune elimination of an entire class of effector T cells.

PubMed 38992254

DOI 10.1038/s41590-024-01899-6

Crossref 10.1038/s41590-024-01899-6

pmc: PMC11291280
pii: 10.1038/s41590-024-01899-6