Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).
Brownlie, R. J. & Zamoyska, R. T cell receptor signalling networks: branched, diversified and bounded. Nat. Rev. Immunol. 13, 257–269 (2013).
Davey, G. M. et al. Preselection thymocytes are more sensitive to T cell receptor stimulation than mature T cells. J. Exp. Med. 188, 1867–1874 (1998).
Gascoigne, N. R., Rybakin, V., Acuto, O. & Brzostek, J. TCR signal strength and T cell development. Annu. Rev. Cell Dev. Biol. 32, 327–348 (2016).
Fu, G. et al. Themis controls thymocyte selection through regulation of T cell antigen receptor-mediated signaling. Nat. Immunol. 10, 848–856 (2009).
Johnson, A. L. et al. Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection. Nat. Immunol. 10, 831–839 (2009).
Lesourne, R. et al. Themis, a T cell-specific protein important for late thymocyte development. Nat. Immunol. 10, 840–847 (2009).
Patrick, M. S. et al. Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes. Proc. Natl. Acad. Sci. USA 106, 16345–16350 (2009).
Kakugawa, K. et al. A novel gene essential for the development of single positive thymocytes. Mol. Cell. Biol. 29, 5128–5135 (2009).
Zvezdova, E. et al. Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability. Sci. Signal. 9, ra51 (2016).
Choi, S. et al. THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1. Nat. Immunol. 18, 433–441 (2017).
Patrussi, L. & Baldari, C. T. Themis releases the brakes on TCR signaling during thymocyte selection by disabling SHP-1. Cell. Mol. Immunol. 14, 724–726 (2017).
Espinoza, J. A., Jara, E. L. & Kalergis, A. M. THEMIS, the new kid on the block for T-cell development. Cell. Mol. Immunol. 14, 721–723 (2017).
Liang, J. et al. Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors. Nat. Commun. 8, 15732 (2017).
Wang, D. et al. Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling. Nat. Immunol. 13, 560–568 (2012).
Yamashita, I., Nagata, T., Tada, T. & Nakayama, T. CD69 cell surface expression identifies developing thymocytes which audition for T cell antigen receptor-mediated positive selection. Int. Immunol. 5, 1139–1150 (1993).
Hare, K. J., Jenkinson, E. J. & Anderson, G. CD69 expression discriminates MHC-dependent and -independent stages of thymocyte positive selection. J. Immunol. 162, 3978–3983 (1999).
Azzam, H. S. et al. CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity. J. Exp. Med. 188, 2301–2311 (1998).
Carpenter, A. C. & Bosselut, R. Decision checkpoints in the thymus. Nat. Immunol. 11, 666 (2010).
Liberzon, A. et al. The molecular signatures database hallmark gene set collection. Cell Syst. 1, 417–425 (2015).
Voll, R. E. et al. NF-κB activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13, 677–689 (2000).
Saini, M. et al. Regulation of Zap70 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci. Signal. 3, ra23 (2010).
Sinclair, C., Bains, I., Yates, A. J. & Seddon, B. Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system. Proc. Natl. Acad. Sci. USA 110, E2905–E2914 (2013).
Cibotti, R., Punt, J. A., Dash, K. S., Sharrow, S. O. & Singer, A. Surface molecules that drive T cell development in vitro in the absence of thymic epithelium and in the absence of lineage-specific signals. Immunity 6, 245–255 (1997).
Gardner, P. Calcium and T lymphocyte activation. Cell 59, 15–20 (1989).
Kortum, R. L., Rouquette-Jazdanian, A. K. & Samelson, L. E. Ras and extracellular signal-regulated kinase signaling in thymocytes and T cells. Trends Immunol. 34, 259–268 (2013).
Fu, G. et al. Themis sets the signal threshold for positive and negative selection in T-cell development. Nature 504, 441–445 (2013).
Surh, C. D. & Sprent, J. Homeostatic T cell proliferation: how far can T cells be activated to self-ligands? J. Exp. Med. 192, F9–F14 (2000).
Canelles, M., Park, M. L., Schwartz, O. M. & Fowlkes, B. J. The influence of the thymic environment on the CD4-versus-CD8 T lineage decision. Nat. Immunol. 4, 756–764 (2003).
Mehta, M. et al. Themis-associated phosphatase activity controls signaling in T cell development. Proc. Natl. Acad. Sci. USA 115, E11331–E11340 (2018).
Paster, W. et al. A THEMIS:SHP1 complex promotes T-cell survival. EMBO J. 34, 393–409 (2015).
Acknowledgements
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).
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Lyu, J., Wang, P., Xu, T. et al. Thymic-specific regulation of TCR signaling by Tespa1. Cell Mol Immunol 16, 897–907 (2019). https://doi.org/10.1038/s41423-019-0259-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41423-019-0259-4
Keywords
This article is cited by
-
Mobilizing ER IP3 receptors as a mechanism to enhance calcium signaling
Cellular & Molecular Immunology (2021)