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

• Published in: The Journal of immunology (1950) Vol. 212; no. 2; pp. 271 - 283
• Main Authors: May, Julia F, Kelly, Rees G, Suen, Alexander Y W, Kim, Jeongbee, Kim, Jeongwoo, Anderson, Colin C, Rayat, Gina R, Baldwin, Troy A
• Format: Journal Article
• Language: English
• Published: United States 15-01-2024
• Subjects: Animals; Antigens; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Central Tolerance; Immune Tolerance; Mice; Programmed Cell Death 1 Receptor - genetics; Thymus Gland
• DOI: 10.4049/jimmunol.2200775
• EISSN: 1550-6606
• ISSN: 0022-1767

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.