Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Department of Immunology, Graduate School of Basic Medical Science, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Front Immunol. 2023 Jun 20;14:1117092. doi: 10.3389/fimmu.2023.1117092. eCollection 2023.
In chronic infections and cancer, exhausted CD8 T cells exhibit heterogeneous subpopulations. TCF1+PD-1+ progenitor exhausted CD8 T cells (Tpex) can self-renew and give rise to Tim-3+PD-1+ terminally differentiated CD8 T cells that retain their effector functions. Tpex cells are thus essential to maintaining a pool of antigen-specific CD8 T cells during persistent antigenic stimulation, and only they respond to PD-1-targeted therapy. Despite their potential as a crucial therapeutic target for immune interventions, the mechanisms controlling the maintenance of virus-specific Tpex cells remain to be determined. We observed approximately 10-fold fewer Tpex cells in the spleens of mice chronically infected with lymphocytic choriomeningitis virus (LCMV) one-year post-infection (p.i.) than at three months p.i. Similar to memory CD8 T cells, Tpex cells have been found to undergo self-renewal in the lymphoid organs, prominently the bone marrow, during chronic LCMV infection. Furthermore, treatment with IL-15 preferentially induced the proliferation of Tpex cells rather than the terminally differentiated subsets. Interestingly, single-cell RNA sequencing analysis of LCMV-specific exhausted CD8 T cells after IL-15 treatment compared with those before treatment revealed increased expression of ribosome-related genes and decreased expression of genes associated with the TCR signaling pathway and apoptosis in both Tpex and Ttex subsets. The exogenous administration of IL-15 to chronically LCMV-infected mice also significantly increased self-renewal of Tpex cells in the spleen and bone marrow. In addition, we assessed the responsiveness of CD8 tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma patients to IL-15. Similar to the data we obtained from chronic viral infection in mice, the expansion of the Tpex subset of PD-1+ CD8 TILs upon IL-15 treatment was significantly higher than that of the terminally differentiated subset. These results show that IL-15 could promote self-renewal of Tpex cells, which has important therapeutic implications.
在慢性感染和癌症中，耗尽的 CD8 T 细胞表现出异质性亚群。TCF1+PD-1+祖细胞耗尽的 CD8 T 细胞（Tpex）可以自我更新，并产生 Tim-3+PD-1+终末分化的 CD8 T 细胞，保留其效应功能。因此，Tpex 细胞对于在持续抗原刺激期间维持抗原特异性 CD8 T 细胞池是必不可少的，只有它们对 PD-1 靶向治疗有反应。尽管它们作为免疫干预的关键治疗靶点具有潜力，但控制病毒特异性 Tpex 细胞维持的机制仍有待确定。我们观察到，在感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）一年后，慢性感染的小鼠脾脏中的 Tpex 细胞数量比感染三个月时减少了约 10 倍。与记忆 CD8 T 细胞类似，Tpex 细胞已被发现在慢性 LCMV 感染期间在淋巴器官（主要是骨髓）中进行自我更新。此外，IL-15 的治疗优先诱导 Tpex 细胞而非终末分化亚群的增殖。有趣的是，与治疗前相比，在用 IL-15 治疗后对 LCMV 特异性耗尽的 CD8 T 细胞进行单细胞 RNA 测序分析时，在 Tpex 和 Ttex 亚群中都发现核糖体相关基因的表达增加，而与 TCR 信号通路和凋亡相关的基因表达减少。IL-15 对慢性 LCMV 感染小鼠的外源性给药也显著增加了脾脏和骨髓中 Tpex 细胞的自我更新。此外，我们评估了肾细胞癌患者 CD8 肿瘤浸润淋巴细胞（TIL）对 IL-15 的反应性。与我们从慢性病毒感染小鼠中获得的数据相似，IL-15 治疗后 PD-1+CD8 TIL 中 Tpex 亚群的扩增明显高于终末分化亚群。这些结果表明，IL-15 可以促进 Tpex 细胞的自我更新，这具有重要的治疗意义。
