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Early TCRα expression generates TCRαγ complexes that signal the DN-to-DP transition and impair development

Nature Immunology volume 3, pages 564–569 (2002)Cite this article

Abstract

Clonotypic T cell receptor (TCR) genes undergo ordered rearrangement and expression in the thymus with the result that TCRα and TCRγ proteins are not expressed in the same cell at the same time. Such “TCRα/γ exclusion” is a feature of normal thymocyte differentiation, but it is abrogated in TCR-transgenic mice, which prematurely express transgenic TCRα proteins in early double-negative (DN) thymocytes. We report here that early expression of TCRα proteins results in the formation of TCRαγ complexes that efficiently signal the differentiation of DN into double-positive thymocytes independently of pre-TCR and TCRβ expression. Thus, abrogation of TCRα/γ exclusion by early TCRα expression results in the formation of isotypically mixed TCRαγ complexes whose in vivo signals circumvent TCRβ selection and redirect thymocyte development along an aberrant developmental pathway.

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Figure 1: Expression of TCRα transgenes results in the generation of TCRβ− DP cells.
Figure 2: Identification of the signaling complex responsible for the generation of TCRβ− DP cells in TCRα-transgenic mice.
Figure 3: Biochemical characterization of TCRαγ complexes.
Figure 4: In vivo reconstruction of a TCRαγ complex in RAG−/− mice that signals the generation of DP thymocytes.
Figure 5: Expression of TCRαγ complexes in developing DN thymocytes does not impair TCRγδ development.

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Acknowledgements

We thank L. Granger, T. Adams and S. Sharrow for expert flow cytometry; D. Winkler for technical assistance; A. Bhandoola for helpful discussions; P. Pereira and R. O'Brien for the Vγ1Cγ4 transgenic mice; D. Raulet for the Vγ2Cγ1 transgenic mice; and R. Bosselut, R. Hodes, P. Love, P. Pereira, D. Singer and D. Wiest for critical reading of the manuscript.

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Authors and Affiliations

  1. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    Batu Erman & Alfred Singer

  2. SAIC Frederick, NCI-Frederick Cancer Research and Development Center, Frederick, 21702, MD, USA

    Lionel Feigenbaum

  3. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, 20892, MD, USA

    John E. Coligan

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  1. Batu Erman
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Correspondence to Alfred Singer.

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Erman, B., Feigenbaum, L., Coligan, J. et al. Early TCRα expression generates TCRαγ complexes that signal the DN-to-DP transition and impair development. Nat Immunol 3, 564–569 (2002). https://doi.org/10.1038/ni800

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