Themis在调节胸腺细胞在T细胞发育过程中的阳性选择方面起着重要作用，但它在外周T细胞中的作用尚不明确。在这里，我们使用依赖他莫昔芬的急性Themis缺失小鼠模型来研究T细胞的激活及其后果。我们发现，增殖、包括抗肿瘤杀伤在内的效应功能以及能量代谢的上调都受到严重影响。这项研究揭示了外周适应Themis缺失现象，通过证明Themis急性缺失后的直接TCR诱导缺陷，在外周T细胞慢性缺乏Themis的dLck-Cre缺失模型中并不明显。我们比较了采用慢性与急性依赖他莫昔芬介导的Themis缺失以及(慢性的)dLck-Cre缺失模型的长期外周适应。我们发现，在慢性依赖他莫昔芬介导的Themis缺失中，T细胞受体(TCR)和细胞因子信号通路的基因表达谱发生了调节。该谱与(慢性的)dLck-Cre缺失模型相重叠。因此，我们发现外周适应会对TCR和细胞因子信号模块产生改变。我们的数据凸显了Themis在CD8+ T细胞激活中的重要性。© 2023 Gautam等人。

Themis is important in regulating positive selection of thymocytes during T cell development, but its role in peripheral T cells is less understood. Here, we investigated T cell activation and its sequelae using a tamoxifen-mediated, acute Themis deletion mouse model. We find that proliferation, effector functions including anti-tumor killing, and up-regulation of energy metabolism are severely compromised. This study reveals the phenomenon of peripheral adaptation to loss of Themis, by demonstrating direct TCR-induced defects after acute deletion of Themis that were not evident in peripheral T cells chronically deprived of Themis in dLck-Cre deletion model. Peripheral adaptation to long-term loss was compared using chronic versus acute tamoxifen-mediated deletion and with the (chronic) dLck-Cre deletion model. We found that upon chronic tamoxifen-mediated Themis deletion, there was modulation in the gene expression profile for both TCR and cytokine signaling pathways. This profile overlapped with (chronic) dLck-Cre deletion model. Hence, we found that peripheral adaptation induced changes to both TCR and cytokine signaling modules. Our data highlight the importance of Themis in the activation of CD8+ T cells.© 2023 Gautam et al.