Capicua (CIC) is a transcriptional repressor that regulates several developmental processes. CIC deficiency results in lymphoproliferative autoimmunity accompanied by expansion of CD44hiCD62Llo effector/memory and follicular Th cell populations. Deletion of Cic alleles in hematopoietic stem cells (Vav1-Cre-mediated knockout of Cic) causes more severe autoimmunity than that caused by the knockout of Cic in CD4+CD8+ double positive thymocytes (Cd4-Cre-mediated knockout of Cic). In this study, we compared splenic CD4+ T cell activation and proliferation between whole immune cell-specific Cic-null (Cicf/f;Vav1-Cre) and T cell-specific Cic-null (Cicf/f;Cd4-Cre) mice. Hyperactivation and hyperproliferation of CD4+ T cells were more apparent in Cicf/f;Vav1-Cre mice than in Cicf/f;Cd4-Cre mice. Cicf/f;Vav1-Cre CD4+ T cells more rapidly proliferated and secreted larger amounts of IL-2 upon TCR stimulation than did Cicf/f;Cd4-Cre CD4+ T cells, while the TCR stimulation-induced activation of the TCR signaling cascade and calcium flux were comparable between them. Mixed wild-type and Cicf/f;Vav1-Cre bone marrow chimeras also exhibited more apparent hyperactivation and hyperproliferation of Cic-deficient CD4+ T cells than did mixed wild-type and Cicf/f;Cd4-Cre bone marrow chimeras. Taken together, our data demonstrate that CIC deficiency at the beginning of T cell development endows peripheral CD4+ T cells with enhanced T cell activation and proliferative capability.

中文翻译：

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造血过程中 Cic 等位基因的缺失时间决定外周 CD4+ T 细胞激活和增殖的程度


Capicua (CIC) 是一种转录抑制因子，可调节多个发育过程。 CIC 缺陷导致淋巴细胞增殖性自身免疫，并伴有 CD44hiCD62Llo 效应/记忆和滤泡 Th 细胞群体的扩张。造血干细胞中 Cic 等位基因的缺失（Vav1-Cre 介导的 Cic 敲除）比 CD4+CD8+ 双阳性胸腺细胞中 Cic 敲除（Cd4-Cre 介导的 Cic 敲除）引起的自身免疫更严重。在本研究中，我们比较了全免疫细胞特异性 Cic-null (Cicf/f;Vav1-Cre) 和 T 细胞特异性 Cic-null (Cicf/f;Cd4-Cre) 小鼠之间的脾 CD4+ T 细胞活化和增殖。 CD4+ T 细胞的过度激活和过度增殖在 Cicf/f;Vav1-Cre 小鼠中比 Cicf/f;Cd4-Cre 小鼠中更为明显。 Cicf/f;Vav1-Cre CD4+ T 细胞在 TCR 刺激后比 Cicf/f;Cd4-Cre CD4+ T 细胞增殖更快，并分泌更多的 IL-2，而 TCR 刺激诱导的 TCR 信号级联激活和它们之间的钙通量相当。与混合野生型和 Cicf/f;Cd4-Cre 骨髓嵌合体相比，混合野生型和 Cicf/f;Vav1-Cre 骨髓嵌合体还表现出更明显的 Cic 缺陷型 CD4+ T 细胞过度活化和过度增殖。综上所述，我们的数据表明，T 细胞发育初期的 CIC 缺陷赋予外周 CD4+ T 细胞增强的 T 细胞活化和增殖能力。