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'Coreceptor tuning': cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR

Nature Immunology volume 8, pages 1049–1059 (2007)Cite this article

Abstract

T cell immunity requires the long-term survival of T cells that are capable of recognizing self antigens but are not overtly autoreactive. How this balance is achieved remains incompletely understood. Here we identify a homeostatic mechanism that transcriptionally tailors CD8 coreceptor expression in individual CD8+ T cells to the self-specificity of their clonotypic T cell receptor (TCR). 'Coreceptor tuning' results from interplay between cytokine and TCR signals, such that signals from interleukin 7 and other common γ-chain cytokines transcriptionally increase CD8 expression and thereby promote TCR engagement of self ligands, whereas TCR signals impair common γ-chain cytokine signaling and thereby decrease CD8 expression. This dynamic interplay induces individual CD8+ T cells to express CD8 in quantities appropriate for the self-specificity of their TCR, promoting the engagement of self ligands, yet avoiding autoreactivity.

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Figure 1: Modulation of CD8 expression on mature CD8+ T cells.
Figure 2: IL-7 upregulates Cd8a transcription.
Figure 3: CD8 upregulation by γc cytokines.
Figure 4: Molecular basis for the low CD8 expression on T cells from HY male mice.
Figure 5: Persistent TCR engagement blocks γc cytokine signaling and suppresses CD8 expression in T cells from HY male mice.
Figure 6: Inverse correlation of TCR signaling intensity and CD8 expression in vivo.
Figure 7: Effect of homeostatic TCR signals on IL-7 signaling and CD8 expression in vivo.
Figure 8: Coreceptor tuning and CD8+ T cell autoreactivity.

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Acknowledgements

We thank R. Gress, R. Hodes, S. Sharrow, N. Taylor, and T. Waldmann for critically reading the manuscript; S. Sharrow, T. Adams and L. Granger for flow cytometry; and Z. Grossman for discussions. Il7−/− mice were provided by the DNAX Research Institute, HY Rag2−/− mice were provided by M. Vacchio (National Institutes of Health), and Ctla4−/−Cd28−/− and Ctla4−/−Cd28+/− mice were provided by A. Sharpe (Harvard Medical School). Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

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  1. Sophia D Sarafova

    Present address: Present address: Biology Department, Davidson College, Davidson, North Carolina 28035, USA.,

Authors and Affiliations

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

    Jung-Hyun Park, Stanley Adoro, Sophia D Sarafova, Amala S Alag, Loretta L Doan & Alfred Singer

  2. Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Stanley Adoro

  3. Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Philip J Lucas

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

    Batu Erman

  5. Immune Cell Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Xiaolong Liu & Remy Bosselut

  6. Institute of Immunology, Medical University of Vienna, Vienna, Austria

    Wilfried Ellmeier

  7. SAIC-Frederick, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, 21702, Maryland, USA

    Lionel Feigenbaum

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Contributions

J.-H.P. conceptualized the research, did experiments, analyzed data and contributed to the writing of the manuscript; S.A., P.J.L, S.D.S. and L.L.D. did experiments and analyzed data; A.S.A. and B.E. constructed some of the experimental mice; X.L. and R.B. provided data; W.E. provided materials; 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., Lucas, P. et al. 'Coreceptor tuning': cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nat Immunol 8, 1049–1059 (2007). https://doi.org/10.1038/ni1512

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