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Thymic-specific regulation of TCR signaling by Tespa1


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.

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We thank Dr. Richard Sloan for helpful discussions and assistance with the manuscript editing. We are grateful to Yewei Li, Jin Chen, and Yingying Huang from the core facilities at the Zhejiang University School of Medicine for technical assistance in the FACS analysis. This work was supported by grants from the National Natural Science Foundation of China (31530019, 31770954, and 31325009 to L.L.), the National Key R&D Program of China (2018YFC1105102) and the Fundamental Research Funds for the Central Universities (2018XZZX001-12).

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J.L., G.F., and L.L. designed the research; J.L., P.W., T.X., Y.S., Z.C., and M.Z. performed the experiments; J.L., G.F., and L.L. analyzed the data; J.L. and L.L. wrote the paper.

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Correspondence to Linrong Lu.

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Lyu, J., Wang, P., Xu, T. et al. Thymic-specific regulation of TCR signaling by Tespa1. Cell Mol Immunol 16, 897–907 (2019).

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