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

TY - JOUR

T1 - Direct presentation of inflammation-associated self-antigens by thymic innate-like T cells induces elimination of autoreactive CD8+ thymocytes

AU - You, Yuanyuan

AU - Dunst, Josefine

AU - Ye, Kewei

AU - Sandoz, Patrick A

AU - Reinhardt, Annika

AU - Sandrock, Inga

AU - Comet, Natalia R

AU - Sarkar, Rupak Dey

AU - Yang, Emily

AU - Duprez, Estelle

AU - Agudo, Judith

AU - Brown, Brian D

AU - Utz, Paul J

AU - Kastenmüller, Wolfgang

AU - Gerlach, Carmen

AU - Prinz, Immo

AU - Önfelt, Björn

AU - Kreslavsky, Taras

N1 - © 2024. The Author(s).

PY - 2024/8

Y1 - 2024/8

N2 - 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.

AB - 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.

KW - Animals

KW - Autoantigens/immunology

KW - CD8-Positive T-Lymphocytes/immunology

KW - Mice

KW - Thymus Gland/immunology

KW - Inflammation/immunology

KW - Antigen Presentation/immunology

KW - Thymocytes/immunology

KW - Mice, Inbred C57BL

KW - Immunity, Innate

KW - Autoimmunity/immunology

KW - Immune Tolerance/immunology

KW - Mice, Transgenic

KW - Mice, Knockout

KW - Lymphocyte Activation/immunology

KW - Eosinophils/immunology

U2 - 10.1038/s41590-024-01899-6

DO - 10.1038/s41590-024-01899-6

M3 - SCORING: Journal article

C2 - 38992254

VL - 25

SP - 1367

EP - 1382

JO - NAT IMMUNOL

JF - NAT IMMUNOL

SN - 1529-2908

IS - 8

ER -