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

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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Figure 1: Identification of gp250 as a candidate positively selecting ligand.
Figure 2: Positive selection of AND TCR–transgenic thymocytes by gp250 in reaggregate cultures.
Figure 3: The gp250-selected CD4SP AND TCR–transgenic T cells are phenotypically and functionally mature.
Figure 4: Positive selection by gp250 has a high degree of specificity.
Figure 5: The gp250 peptide does not stimulate the proliferation of peripheral AND TCR–transgenic T cells in vitro.
Figure 6: The gp250 peptide acts as a coagonist for peripheral AND TCR–transgenic T cells.
Figure 7: The gp250 peptide enhances the survival of homeostatically proliferating AND TCR–transgenic 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.).

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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.

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Correspondence to Paul M Allen.

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Lo, WL., Felix, N., Walters, J. et al. An endogenous peptide positively selects and augments the activation and survival of peripheral CD4+ T cells. Nat Immunol 10, 1155–1161 (2009). https://doi.org/10.1038/ni.1796

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