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Themis controls thymocyte selection through regulation of T cell antigen receptor–mediated signaling

Nature Immunology volume 10, pages 848–856 (2009)Cite this article

Abstract

Themis (thymocyte-expressed molecule involved in selection), a member of a family of proteins with unknown functions, is highly conserved among vertebrates. Here we found that Themis had high expression in thymocytes between the pre–T cell antigen receptor (pre-TCR) and positive-selection checkpoints and low expression in mature T cells. Themis-deficient thymocytes showed defective positive selection, which resulted in fewer mature thymocytes. Negative selection was also impaired in Themis-deficient mice. A greater percentage of Themis-deficient T cells had CD4+CD25+Foxp3+ regulatory and CD62LloCD44hi memory phenotypes than did wild-type T cells. In support of the idea that Themis is involved in TCR signaling, this protein was phosphorylated quickly after TCR stimulation and was needed for optimal TCR-driven calcium mobilization and activation of the kinase Erk.

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Figure 1: Structure, expression and localization of Themis in wild-type mice.
Figure 2: Defective positive selection in Themis−/− mice.
Figure 3: Negative selection defect in Themis−/− mice.
Figure 4: Phenotype of peripheral T cells in Themis−/− mice.
Figure 5: Defective activation of Themis-deficient T cells.
Figure 6: Themis is part of the TCR signal cascade.
Figure 7: Signaling in Themis-deficient thymocytes.

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Acknowledgements

We thank J. Bradley, A. Field, Y. Mondal, S. Rose, W. Sakati, V. Sharma, J. Shepherd and J. Vasquez for technical help. Supported by the US National Institutes of Health (GM048002 and AI073870 to N.R.J.G. and T32 AI07244 to M.V.M. and J.A.H.H.), the Concern Foundation for Cancer Research (S.V.), American Chemical Society (Irving S. Sigal Fellowship to J.A.H.H.), the Wellcome Trust (GR076558MA to O.A., C.B. and M.S.), the Sir William Dunn School of Pathology (O.A., C.B. and M.S.) and Lincoln College, Oxford (Sloane Robinson Graduate Award to C.B.). This is manuscript 19524 from The Scripps Research Institute.

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Author notes

  1. Marielena V McGuire, Paul R Fallen, Yina H Huang & Howard S Fox

    Present address: Present addresses: United States Army Medical Research and Materiel Command, Fort Detrick, Maryland, USA (M.V.M.); Oxford Gene Technology, Begbroke Science Park, Oxford, UK (P.R.F.); Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA (Y.H.H.); and Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska, USA (H.S.F.).,

  2. Guo Fu and Sébastien Vallée: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA

    Guo Fu, Sébastien Vallée, Vasily Rybakin, Marielena V McGuire, Jeanette Ampudia, Paul R Fallen, John A H Hoerter, Anil Munshi, Yina H Huang, Jianfang Hu, Karsten Sauer & Nicholas R J Gascoigne

  2. T cell Signalling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

    Claudia Brockmeyer, Mogjiborahman Salek & Oreste Acuto

  3. Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, La Jolla, California, USA

    Howard S Fox

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Contributions

N.R.J.G., M.V.M., S.V. and G.F. designed the project; M.V.M. cloned Themis and did initial gene-sequencing and expression analysis; G.F., S.V., V.R. and J.A. did the main part of the study analyzing the Themis-deficient mice, with contributions from J.A.H.H., A.M. and J.H.; P.R.F. constructed the Themis targeting vector and did expression studies; C.B., M.S. and O.A. identified and analyzed human Themis phosphorylation; Y.H.H. and K.S. helped with T cell signaling assays; H.S.F. did the in situ hybridization; N.R.J.G. and S.V. wrote the manuscript with contributions from G.F., V.R., K.S., O.A., A.M. and M.V.M.; and G.F., S.V., V.R., C.B., J.A.H.H. and N.R.J.G. prepared figures.

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Correspondence to Nicholas R J Gascoigne.

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Fu, G., Vallée, S., Rybakin, V. et al. Themis controls thymocyte selection through regulation of T cell antigen receptor–mediated signaling. Nat Immunol 10, 848–856 (2009). https://doi.org/10.1038/ni.1766

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