Thymic negative selection of the T cell receptor (TCR) repertoire is essential for establishing self-tolerance and acquired allograft tolerance following organ transplantation. However, it is unclear whether and how peripheral clonal deletion of alloreactive T cells induces transplantation tolerance. Here, we establish that programmed cell death protein 1 (PD-1) is a hallmark of alloreactive T cells and is associated with clonal expansion after alloantigen encounter. Moreover, we found that diphtheria toxin receptor (DTR)–mediated ablation of PD-1⁺ cells reshaped the TCR repertoire through peripheral clonal deletion of alloreactive T cells and promoted tolerance in mouse transplantation models. In addition, by using PD-1–specific depleting antibodies, we found that antibody-mediated depletion of PD-1⁺ cells prevented heart transplant rejection and the development of experimental autoimmune encephalomyelitis (EAE) in humanized PD-1 mice. Thus, these data suggest that PD-1 is an attractive target for peripheral clonal deletion and induction of immune tolerance.

中文翻译：

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PD-1 表达细胞的靶向清除通过外周克隆缺失诱导免疫耐受

T 细胞受体 (TCR) 库的胸腺阴性选择对于器官移植后建立自我耐受和获得性同种异体移植耐受至关重要。然而，尚不清楚同种异体反应性 T 细胞的外周克隆缺失是否以及如何诱导移植耐受。在这里，我们确定程序性细胞死亡蛋白 1 (PD-1) 是同种异体反应性 T 细胞的标志，并且与同种异体抗原相遇后的克隆扩张相关。此外，我们发现白喉毒素受体（DTR）介导的 PD-1 ⁺细胞消融通过同种异体反应性 T 细胞的外周克隆删除重塑了 TCR 库，并促进了小鼠移植模型的耐受性。此外，通过使用 PD-1 特异性耗竭抗体，我们发现抗体介导的 PD-1 ⁺细胞耗竭可防止心脏移植排斥和人源化 PD-1 小鼠中实验性自身免疫性脑脊髓炎 (EAE) 的发展。因此，这些数据表明 PD-1 是外周克隆删除和诱导免疫耐受的有吸引力的靶标。