Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
J Immunol. 2024 Jan 15;212(2):271-283. doi: 10.4049/jimmunol.2200775.
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.
高亲和力 TCR 信号的接收会通过中枢和外周耐受机制从库中消除高度自身反应性 T 细胞。克隆删除被认为是中枢耐受的主要驱动因素；然而，已经描述了其他机制，如诱导调节性 T 细胞和功能障碍。对这些不同中枢耐受机制之间相互作用的理解仍然缺乏。我们之前表明，对模型组织限制性 Ag 的克隆删除受损不会损害耐受。在这项研究中，我们确定未能发生克隆删除的小鼠 T 细胞在胸腺中功能受损。程序性细胞死亡蛋白 1（PD-1）在胸腺中被诱导，并在不依赖于克隆删除的情况下，在 CD8+胸腺细胞中建立对组织限制性 Ag 的细胞内自身耐受是必需的。在骨髓嵌合体中，在 PD-L1 缺陷型受体中未观察到耐受，但是在将耐受的胸腺细胞或 T 细胞过继转移至 PD-L1 缺陷型受体后，耐受得到了很大程度的维持。然而，CRISPR 介导的耐受 T 细胞中 PD-1 的缺失导致耐受中断，这表明建立和维持耐受需要不同的 PD-1 信号传导要求。最后，我们表明，高亲和力 Ag 的慢性暴露支持耐受的长期维持。总之，我们的研究确定了 PD-1 在逃避克隆删除的自身反应性 T 细胞中建立中枢耐受中的关键作用。它还揭示了抗 PD-1 通路免疫检查点阻断和免疫相关不良事件发展的潜在作用机制。
