Institute of Immunology and Department of Dermatology and Rheumatology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China.
Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, 310058, Hangzhou, China.
Cell Mol Immunol. 2019 Dec;16(12):897-907. doi: 10.1038/s41423-019-0259-4. Epub 2019 Jul 17.
Double-positive (DP) thymocytes undergo positive selection to become mature single-positive CD4 and CD8 T cells in response to T cell receptor (TCR) signaling. Unlike mature T cells, DP cells must respond to low-affinity self-peptide-MHC ligands before full upregulation of their surface TCR expression can occur. Thus, DP thymocytes must be more sensitive to ligands than mature T cells. A number of molecules have been found that are able to enhance the strength of the TCR signal to facilitate positive selection. However, almost all of these molecules are also active in mature T cells. Themis (thymocyte expressed molecule involved in selection) and Tespa1 (thymocyte expressed positive selection associated 1) are two recently discovered molecules essential for optimal TCR signaling and thymocyte development. A deficiency in both molecules leads to defects in positive selection. Here, we compared the relative contributions of Themis and Tespa1 to positive selection in thymocytes. We show that Tespa1 deficiency led to more limited and specific gene expression profile changes in cells undergoing positive selection. In mixed bone marrow transfer experiments, Tespa1 cells showed more severe defects in thymocyte development than Themis cells. However, Tespa1 cells showed a substantial degree of homeostatic expansion and became predominant in the peripheral lymphoid organs, suggesting that Tespa1 is a thymic-specific TCR signaling regulator. This hypothesis is further supported by our observations in Tespa1 conditional knockout mice, as Tespa1 deletion in peripheral T cells did not affect TCR signaling or cell proliferation. The different regulatory effects of Tespa1 and Themis are in accordance with their nonredundant roles in thymocyte selection, during which Tespa1 and Themis double knockouts showed additive defects.
双阳性 (DP) 胸腺细胞在 T 细胞受体 (TCR) 信号的作用下经历阳性选择，成为成熟的单阳性 CD4 和 CD8 T 细胞。与成熟 T 细胞不同，DP 细胞在其表面 TCR 表达完全上调之前，必须对低亲和力自身肽-MHC 配体作出反应。因此，DP 胸腺细胞必须比成熟 T 细胞对配体更敏感。已经发现了许多能够增强 TCR 信号强度以促进阳性选择的分子。然而，几乎所有这些分子在成熟 T 细胞中也具有活性。Themis（参与选择的胸腺细胞表达分子）和 Tespa1（胸腺细胞表达的阳性选择相关 1）是最近发现的两个对最佳 TCR 信号和胸腺细胞发育至关重要的分子。这两种分子的缺乏都会导致阳性选择缺陷。在这里，我们比较了 Themis 和 Tespa1 对胸腺细胞阳性选择的相对贡献。我们发现 Tespa1 缺陷导致经历阳性选择的细胞中基因表达谱的变化更有限和特定。在混合骨髓移植实验中，Tespa1 细胞在胸腺细胞发育方面的缺陷比 Themis 细胞更为严重。然而，Tespa1 细胞表现出相当程度的同源性扩张，并在周围淋巴器官中占据主导地位，这表明 Tespa1 是一种胸腺特异性 TCR 信号调节因子。这一假设进一步得到了我们在 Tespa1 条件性敲除小鼠中观察结果的支持，因为 Tespa1 在周围 T 细胞中的缺失不影响 TCR 信号或细胞增殖。Tespa1 和 Themis 的不同调节作用与其在胸腺细胞选择中的非冗余作用一致，在 Tespa1 和 Themis 双敲除小鼠中观察到了累加缺陷。
