Establishment of CD8+ T Cell Thymic Central Tolerance to Tissue-Restricted Antigen Requires PD-1.

Autor:	May JF; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada., Kelly RG; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada., Suen AYW; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada., Kim J; Department of Surgery, University of Alberta, Edmonton, Alberta, Canada., Kim J; Department of Surgery, University of Alberta, Edmonton, Alberta, Canada., Anderson CC; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.; Department of Surgery, University of Alberta, Edmonton, Alberta, Canada., Rayat GR; Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.; Ray Rajotte Surgical-Medical Research Institute, AB Diabetes and Transplant Institutes, University of Alberta, Edmonton, Alberta, Canada., Baldwin TA; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2024 Jan 15; Vol. 212 (2), pp. 271-283.
DOI:	10.4049/jimmunol.2200775
Abstrakt:	Highly self-reactive T cells are censored from the repertoire by both central and peripheral tolerance mechanisms upon receipt of high-affinity TCR signals. Clonal deletion is considered a major driver of central tolerance; however, other mechanisms such as induction of regulatory T cells and functional impairment have been described. An understanding of the interplay between these different central tolerance mechanisms is still lacking. We previously showed that impaired clonal deletion to a model tissue-restricted Ag did not compromise tolerance. In this study, we determined that murine T cells that failed clonal deletion were rendered functionally impaired in the thymus. Programmed cell death protein 1 (PD-1) was induced in the thymus and was required to establish cell-intrinsic tolerance to tissue-restricted Ag in CD8+ thymocytes independently of clonal deletion. In bone marrow chimeras, tolerance was not observed in PD-L1-deficient recipients, but tolerance was largely maintained following adoptive transfer of tolerant thymocytes or T cells to PD-L1-deficient recipients. However, CRISPR-mediated ablation of PD-1 in tolerant T cells resulted in broken tolerance, suggesting different PD-1 signaling requirements for establishing versus maintaining tolerance. Finally, we showed that chronic exposure to high-affinity Ag supported the long-term maintenance of tolerance. Taken together, our study identifies a critical role for PD-1 in establishing central tolerance in autoreactive T cells that escape clonal deletion. It also sheds light on potential mechanisms of action of anti-PD-1 pathway immune checkpoint blockade and the development of immune-related adverse events. (Copyright © 2024 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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