Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
Institute of Convergence Science, Yonsei University, Seoul, Republic of Korea.
Elife. 2021 Dec 13;10:e71769. doi: 10.7554/eLife.71769.
Central tolerance is achieved through positive and negative selection of thymocytes mediated by T cell receptor (TCR) signaling strength. Thus, dysregulation of the thymic selection process often leads to autoimmunity. Here, we show that Capicua (CIC), a transcriptional repressor that suppresses autoimmunity, controls the thymic selection process. Loss of CIC prior to T-cell lineage commitment impairs both positive and negative selection of thymocytes. CIC deficiency attenuated TCR signaling in CD4CD8 double-positive (DP) cells, as evidenced by a decrease in CD5 and phospho-ERK levels and calcium flux. We identified , , and as CIC target genes that could inhibit TCR signaling in DP cells. Furthermore, impaired positive selection and TCR signaling were partially rescued in and double mutant mice. Our findings indicate that CIC is a transcription factor required for thymic T cell development and suggests that CIC acts at multiple stages of T cell development and differentiation to prevent autoimmunity.
中央耐受性是通过 T 细胞受体 (TCR) 信号强度介导的胸腺细胞的阳性和阴性选择来实现的。因此，胸腺选择过程的失调常常导致自身免疫。在这里，我们表明，Capicua（CIC），一种抑制自身免疫的转录抑制剂，控制着胸腺选择过程。在 T 细胞谱系承诺之前失去 CIC 会损害胸腺细胞的阳性和阴性选择。CIC 缺乏会减弱 CD4CD8 双阳性 (DP) 细胞中的 TCR 信号，这表现在 CD5 和磷酸化 ERK 水平以及钙通量的降低。我们鉴定出 CIC 的靶基因 、 、 和 ，它们可以抑制 DP 细胞中的 TCR 信号。此外，在 和 双突变小鼠中，受损的阳性选择和 TCR 信号部分得到了挽救。我们的研究结果表明，CIC 是一种转录因子，是胸腺 T 细胞发育所必需的，这表明 CIC 可以在 T 细胞发育和分化的多个阶段发挥作用，以预防自身免疫。
