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Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling

Nature Immunology volume 13, pages 560–568 (2012)Cite this article

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Abstract

Signaling via the T cell antigen receptor (TCR) during the CD4+CD8+ double-positive developmental stage determines thymocyte selection and lineage commitment. Here we describe a previously uncharacterized T cell–expressed protein, Tespa1, with critical functions during the positive selection of thymocytes. Tespa1−/− mice had fewer mature thymic CD4+ and CD8+ T cells, which reflected impaired thymocyte development. Tespa1 associated with the TCR signaling components PLC-γ1 and Grb2, and Tespa1 deficiency resulted in attenuated TCR signaling, as reflected by defective activation of the Erk–AP-1 and Ca2+-NFAT pathways. Our findings demonstrate that Tespa1 is a component of the TCR signalosome and is essential for T cell selection and maturation through the regulation of TCR signaling during T cell development.

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Figure 1: Structure, expression and subcellular localization of Tespa1.
Figure 2: Defective T cell development in Tespa1−/− mice.
Figure 3: Impaired development of SP thymocytes in Tespa1−/− mice.
Figure 4: Defective positive selection in Tespa1−/− mice.
Figure 5: Phenotype of peripheral T cells in Tespa1−/− mice.
Figure 6: Impaired MHC-restricted thymocyte differentiation in Tespa1−/− mice.
Figure 7: Defective activation of Tespa1-deficient T cells.
Figure 8: Interruption of TCR-driven Erk activation and calcium signaling in Tespa1−/− thymocytes.
Figure 9: Involvement of Tespa1 in the Lat signalosome.

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Acknowledgements

We thank X. Li, C. Xu and B. Li for discussions; H. Cantor, Y. Ke and H. Hu for critical reading; and A. Alison for assistance with manuscript editing. Supported by the National Natural Science Foundation of China (30972724 and 31070782 to L.L., and 30901311 and 31170842 to D.W.), the Zhejiang Provincial Natural Science Foundation of China (R2090202 to L.L., and Y2090401 to D.W.) and the National Basic Research Program of China (973 Program; 2011CB944100 and 2012CB945004 to L.L.).

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  1. Di Wang and Mingzhu Zheng: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China

    Di Wang, Mingzhu Zheng, Lei Lei, Yunliang Yao, Yuanjun Qiu, Lie Ma, Jun Lou, Chuan Ouyang, Lie Wang, Jianli Wang, Xuetao Cao & Linrong Lu

  2. Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou, China

    Di Wang, Mingzhu Zheng, Lei Lei, Yunliang Yao, Yuanjun Qiu, Lie Ma, Jun Lou, Chuan Ouyang, Xue Zhang & Linrong Lu

  3. Institute of Feed Science, Zhejiang University School of Medicine, Hangzhou, China

    Jian Ji

  4. Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China

    Xue Zhang

  5. Shanghai Research Center for Model Organisms, Shanghai, China

    Yuewei He, Jun Chi & Ying Kuang

  6. Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China

    Xuetao Cao

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Contributions

D.W., M.Z., L.W., Y.K., J.W., X.C. and L. Lu. designed research; D.W., M.Z., L. Lei., J.J., Y.Y., Y.Q., L.M., J.L., C.O., X.Z., Y.H., J.C. and L. Lu. did research; D.W., M.Z., L.W. and L. Lu. analyzed data; and D.W., M.Z. and L. Lu. wrote the paper.

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Correspondence to Linrong Lu.

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Supplementary Figures 1–9 (PDF 4861 kb)

Supplementary Table 1

Genes differentially expressed in CD69+ Tespa1+/+ and Tespa1-/- thymocytes. (XLSX 291 kb)

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Wang, D., Zheng, M., Lei, L. et al. Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling. Nat Immunol 13, 560–568 (2012). https://doi.org/10.1038/ni.2301

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