Article ; Online: Establishment of CD8+ T Cell Thymic Central Tolerance to Tissue-Restricted Antigen Requires PD-1.
Journal of immunology (Baltimore, Md. : 1950)
2023 Volume 212, Issue 2, Page(s) 271–283
Abstract: 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 ...
| Abstract | 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. |
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| MeSH term(s) | Mice ; Animals ; B7-H1 Antigen ; Programmed Cell Death 1 Receptor/genetics ; Central Tolerance ; CD8-Positive T-Lymphocytes ; Thymus Gland ; Antigens ; Immune Tolerance |
| Chemical Substances | B7-H1 Antigen ; Programmed Cell Death 1 Receptor ; Antigens |
| Language | English |
| Publishing date | 2023-11-20 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 3056-9 |
| ISSN | 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381 |
| ISSN (online) | 1550-6606 |
| ISSN | 0022-1767 ; 1048-3233 ; 1047-7381 |
| DOI | 10.4049/jimmunol.2200775 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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