Laboratory of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
J Immunol. 2020 May 15;204(10):2671-2684. doi: 10.4049/jimmunol.1801243. Epub 2020 Apr 1.
TCR signaling is required for homeostasis of naive αβ T cells. However, whether such a signal is necessary for γδ T cell homeostasis in the periphery remains unknown. In this study, we present evidence that a portion of Vγ2 γδ T cells, one of the major γδ T cell subsets in the secondary lymphoid organs, requires TCR signaling for homeostasis. To attenuate γδTCR signals, we generated mice lacking Eγ4 (Eγ4), an enhancer located at the 3'-most end of the TCRγ locus. Overall, we found that in thymus, Eγ4 loss altered V-J rearrangement, chromatin accessibility, and transcription of the TCRγ locus in a distance-dependent manner. Vγ2 γδ T cells in Eγ4 mice developed normally both fetal and adult mouse thymi but were relatively reduced in number in spleen and lymph nodes. Although Vγ2 TCR transcription decreased in all subpopulations of Eγ4 mice, the number of Vγ2 γδ T cells decreased and TCR signaling was attenuated only in the innate-like CD27CD45RB subpopulation in peripheral lymphoid organs. Consistently, CD27CD45RB Vγ2 γδ T cells from Eγ4 mice transferred into Rag2-deficient mice were not efficiently recovered, suggesting that continuous TCR signaling is required for their homeostasis. Finally, CD27CD45RB Vγ2 γδ T cells from Eγ4 mice showed impaired TCR-induced activation and antitumor responses. These results suggest that normal homeostasis of innate-like CD27CD45RB Vγ2 γδ T cells in peripheral lymphoid organs requires TCR signaling.
T 细胞受体 (TCR) 信号对于初始 αβ T 细胞的稳态是必需的。然而，外周 γδ T 细胞的稳态是否需要这种信号仍然未知。在这项研究中，我们提供了证据表明，次级淋巴器官中主要 γδ T 细胞亚群之一的 Vγ2 γδ T 细胞的一部分需要 TCR 信号来维持其稳态。为了减弱 γδTCR 信号，我们生成了缺乏 Eγ4（Eγ4）的小鼠，Eγ4 是 TCRγ 基因座 3'-末端的一个增强子。总的来说，我们发现 Eγ4 缺失以距离依赖的方式改变了 TCRγ 基因座的 V-J 重排、染色质可及性和转录。Eγ4 小鼠的 Vγ2 γδ T 细胞在胎儿和成年小鼠胸腺中正常发育，但在脾和淋巴结中的数量相对减少。尽管 Eγ4 小鼠所有亚群的 Vγ2 TCR 转录均降低，但只有在周围淋巴器官中的固有样 CD27CD45RB 亚群中，Vγ2 γδ T 细胞的数量减少且 TCR 信号被减弱。一致地，从 Eγ4 小鼠中转移到 Rag2 缺陷型小鼠的 CD27CD45RB Vγ2 γδ T 细胞不能有效地恢复，表明它们的稳态需要持续的 TCR 信号。最后，Eγ4 小鼠的 CD27CD45RB Vγ2 γδ T 细胞显示出 TCR 诱导的激活和抗肿瘤反应受损。这些结果表明，外周淋巴器官中固有样 CD27CD45RB Vγ2 γδ T 细胞的正常稳态需要 TCR 信号。
