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An endogenous peptide positively selects and augments the activation and survival of peripheral CD4+ T cells

Nature Immunology volume 10, pages 11551161 (2009) | Download Citation

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Abstract

Although CD4+ and CD8+ T cells differ in the strength of their positively selecting signal, endogenous positively selecting ligands have been identified only for major histocompatibility complex (MHC) class I–restricted T cell antigen receptors (TCRs). Here we screened for ligands able to positively select MHC class II–restricted TCRs using thymocytes from four I-Ek-restricted TCR-transgenic mice and a large panel of self peptides. One peptide, gp250, induced positive selection of AND CD4+ T cells, had no homology with the AND TCR agonist ligand and was recognized with a high degree of specificity. The gp250 peptide acted as a coagonist to initiate the activation and enhance the survival of peripheral AND CD4+ T cells. Thus, positively selecting ligands are critical in thymocyte development and in the activation and maintenance of peripheral T cells.

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Acknowledgements

We thank A.G. Farr (University of Washington) for ANV41.2 cells; B. Stockinger (Medical Research Council National Institute for Medical Research) for the A1 TCR–transgenic mouse; C.D. Surh for advice on homeostatic proliferation; D. Kreamalmeyer for maintaining the mouse colony; S. Horvath for peptide synthesis and purification; C. Morley for suggestions and reading the manuscript; and G. Morris, D. Donermeyer, E. Unanue, C. Hsieh and Y. Huang for critical reading of the manuscript and comments. Supported by the US National Institutes of Health (AI-24157 to P.M.A. and 2P41 RR 000954 to M.L.G.).

Author information

Author notes

    • Nathan J Felix
    •  & James J Walters

    Present addresses: Bristol-Myers Squibb, Princeton, New Jersey, USA (N.J.F.) and Sigma-Aldrich, St. Louis, Missouri, USA (J.J.W.).

    • Wan-Lin Lo
    •  & Nathan J Felix

    These authors contributed equally to this work.

Affiliations

  1. Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Wan-Lin Lo
    • , Nathan J Felix
    •  & Paul M Allen
  2. Department of Chemistry, Washington University, St. Louis, Missouri, USA.

    • James J Walters
    • , Henry Rohrs
    •  & Michael L Gross

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Contributions

W.-L.L., N.J.F. and P.M.A. designed the study and wrote the manuscript; J.J.W., H.R. and M.L.G. identified all of the self-peptides by liquid chromatography–tandem mass spectrometry and analyzed the synthetic peptides; and W.-L.L. and N.J.F. did all of the in vitro and in vivo experimental work.

Corresponding author

Correspondence to Paul M Allen.

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https://doi.org/10.1038/ni.1796

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