Benaroya Research Institute.
J Immunol. 2024 Jul 1;213(1):52-62. doi: 10.4049/jimmunol.2300262.
The thymus is an important site for the establishment of an appropriate immune response through positive and negative selection of developing T cells. During selection, developing T cells interact with cortical and medullary thymic epithelial cells (TECs), termed cTECs and mTECs, respectively. Using a Foxn1Cre+/-SKIfl/fl mouse model, we found that TEC-specific deletion of SKI reduced the mTEC compartment in the thymus and that tissue-restricted Ag expression in mTECs was altered. This decrease in the medullary area led to a decrease in CD4 thymocyte cellularity; however, mature CD4 cellularity in the spleen remained normal. Interestingly, naive CD4 T cells purified from SKI-deleted mice showed a defect in proliferation in vitro after global TCR stimulation, and these mice were significantly protected from developing experimental autoimmune encephalomyelitis compared with the control mice. Overall, our findings suggest that SKI signaling in the thymus regulates mTEC differentiation and function as well as downstream peripheral T cell responses and provide evidence for targeting SKI in T cell-driven autoimmune diseases such as multiple sclerosis.
胸腺是通过对发育中的 T 细胞进行阳性和阴性选择来建立适当免疫反应的重要场所。在选择过程中，发育中的 T 细胞与皮质和髓质胸腺上皮细胞（TEC）相互作用，分别称为 cTEC 和 mTEC。使用 Foxn1Cre+/-SKIfl/fl 小鼠模型，我们发现 TEC 特异性缺失 SKI 会减少胸腺中的 mTEC 区室，并且 mTEC 中的组织限制性 Ag 表达发生改变。这种髓质区域的减少导致 CD4 胸腺细胞细胞数量减少；然而，脾脏中成熟的 CD4 细胞数量仍保持正常。有趣的是，从 SKI 缺失的小鼠中纯化的幼稚 CD4 T 细胞在体外经全局 TCR 刺激后增殖出现缺陷，与对照小鼠相比，这些小鼠在发生实验性自身免疫性脑脊髓炎方面受到显著保护。总体而言，我们的研究结果表明，胸腺中的 SKI 信号转导调节 mTEC 分化和功能以及下游外周 T 细胞反应，并为靶向多发性硬化症等 T 细胞驱动的自身免疫性疾病中的 SKI 提供了证据。
