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Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells

Nature Immunology volume 11, pages 257–264 (2010)Cite this article

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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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Figure 1: Impaired CD8+ T cell generation in Stat5a- and Stat5b-deficient mice.
Figure 2: The generation of CD8+ T cells requires STAT-mediated cytokine signaling.
Figure 3: IL-7 signaling induces Runx3, which specifies CD8 lineage choice.
Figure 4: Effect of in vitro IL-7 signaling on cytokine-responsive preselection DP thymocytes.
Figure 5: In vivo IL-7 signaling of 7SZ thymocytes induces their differentiation into mature CD8+ T cells.
Figure 6: Transgenic IL-7 expression induces efficient CD8+ T cell differentiation in 7SZ mice.

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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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Authors and Affiliations

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

    Jung-Hyun Park, Stanley Adoro, Terry Guinter, Amala S Alag, Motoko Y Kimura & Alfred Singer

  2. Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey

    Batu Erman

  3. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Marta Catalfamo

  4. Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Yongzhi Cui & Lothar Hennighausen

  5. Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Philip J Lucas & Ronald E Gress

  6. Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Kanagawa, Japan

    Masato Kubo

  7. Science Applications International Corporation-Frederick, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, Maryland, USA

    Lionel Feigenbaum

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Contributions

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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Correspondence to Alfred Singer.

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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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