Graduate School of Information Sciences, Tohoku University, Sendai, Japan.
Faculty of Core Research, Ochanomizu University, Tokyo, Japan.
PLoS One. 2022 Sep 9;17(9):e0274494. doi: 10.1371/journal.pone.0274494. eCollection 2022.
T cell exhaustion is a state of T cell dysfunction during chronic infection and cancer. Antibody-targeting immune checkpoint inhibitors to reverse T cell exhaustion is a promising approach for cancer immunotherapy. However, molecular mechanisms of T cell exhaustion remain incompletely understood. Here, we performed a transcriptome analysis by integrating seven exhaustion datasets caused by multiple diseases in both humans and mice. In this study, an overlap of 21 upregulated and 37 downregulated genes was identified in human and mouse exhausted CD8+ T cells. These genes were significantly enriched in exhaustion response-related pathways, such as signal transduction, immune system processes, and regulation of cytokine production. Gene expression network analysis revealed that the well-documented exhaustion genes were defined as hub genes in upregulated genes. In addition, a weighted gene co-expression analysis identified 175 overlapping genes that were significantly correlated with the exhaustion trait in both humans and mice. This study found that overlapping six genes were significantly upregulated and highly related to T cell exhaustion. Finally, we revealed that CD200R1 and ADGRG1, less described previously in exhaustion, contributed to T cell exhaustion. Overall, our findings reveal the mechanisms of T cell exhaustion and provide an important reference to the immunology community.
T 细胞耗竭是慢性感染和癌症中 T 细胞功能障碍的一种状态。抗体靶向免疫检查点抑制剂来逆转 T 细胞耗竭是癌症免疫治疗的一种有前途的方法。然而，T 细胞耗竭的分子机制仍不完全清楚。在这里，我们通过整合人类和小鼠多种疾病引起的七个耗竭数据集进行了转录组分析。在这项研究中，在人类和小鼠耗竭的 CD8+T 细胞中鉴定出 21 个上调和 37 个下调基因的重叠。这些基因在耗竭反应相关途径中显著富集，如信号转导、免疫系统过程和细胞因子产生的调节。基因表达网络分析表明，已被充分描述的耗竭基因被定义为上调基因中的枢纽基因。此外，加权基因共表达分析鉴定出 175 个在人类和小鼠中与耗竭特征显著相关的重叠基因。这项研究发现，六个重叠基因显著上调，与 T 细胞耗竭高度相关。最后，我们揭示了以前在耗竭中描述较少的 CD200R1 和 ADGRG1 有助于 T 细胞耗竭。总的来说，我们的研究结果揭示了 T 细胞耗竭的机制，并为免疫学领域提供了重要的参考。
