Abstract
Immature CD4+CD8+ (double-positive (DP)) thymocytes are signaled via T cell antigen receptors (TCRs) to undergo positive selection and become responsive to intrathymic cytokines such as interleukin 7 (IL-7). We report here that cytokine signaling is required for positively selected thymocytes to express the transcription factor Runx3, specify CD8 lineage choice and differentiate into cytotoxic-lineage T cells. In DP thymocytes genetically engineered to be cytokine responsive, IL-7 signaling induced TCR-unsignaled DP thymocytes to express Runx3 and to differentiate into mature CD8+ T cells, completely circumventing positive selection. We conclude that TCR-mediated positive selection converts DP cells into cytokine-responsive thymocytes, but it is subsequent signaling by intrathymic cytokines that specifies CD8 lineage choice and promotes differentiation into cytotoxic-lineage T cells.
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Acknowledgements
We thank R. Bosselut, N. El Kassar, R. Hodes, D. Singer and N. Taylor for critical reading of the manuscript; S. Habu (Tokai University) for mouse Runx3 cDNA; A. Weiss (University of California San Francisco) for fluorescein isothiocyanate–conjugated monoclonal antibody to Syk (5F5); J. Ihle (St. Jude Children's Research Hospital) for Socs1+/−Ifng−/− mice; and S. Sharrow, A. Adams and L. Granger for flow cytometry. Supported by the Intramural Research Program of the US National Institutes of Health, the National Cancer Institute and the Center for Cancer Research.
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J.-H.P. did experiments, analyzed data and contributed to the writing of the manuscript; S.A., T.G., M.C., M.Y.K. and P.J.L. did experiments and analyzed data; B.E. and A.S.A. constructed some of the experimental mice; Y.C., R.E.G., M.K. and L.H. provided experimental mice; L.F. generated transgenic mice; and A.S. conceptualized the research, directed the study, analyzed data and wrote the manuscript.
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Park, JH., Adoro, S., Guinter, T. et al. Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nat Immunol 11, 257–264 (2010). https://doi.org/10.1038/ni.1840
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DOI: https://doi.org/10.1038/ni.1840
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