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IL-7 signaling must be intermittent, not continuous, during CD8+ T cell homeostasis to promote cell survival instead of cell death

An Erratum to this article was published on 16 January 2015

Abstract

The maintenance of naive CD8+ T cells is necessary for lifelong immunocompetence but for unknown reasons requires signaling via both interleukin 7 (IL-7) and the T cell antigen receptor (TCR). We now report that naive CD8+ T cells required IL-7 signaling to be intermittent, not continuous, because prolonged IL-7 signaling induced naive CD8+ T cells to proliferate, produce interferon-γ (IFN-γ) and undergo IFN-γ-triggered cell death. Homeostatic engagement of the TCR interrupted IL-7 signaling and thereby supported the survival and quiescence of CD8+ T cells. However, CD8+ T cells with insufficient TCR affinity for self ligands received prolonged IL-7 signaling and died during homeostasis. In this study we identified regulation of the duration of IL-7 signaling by homeostatic engagement of the TCR as the basis for in vivo CD8+ T cell homeostasis.

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Figure 1: Effect of continuous IL-7 signaling on the proliferation and survival of naive CD8+ T cells.
Figure 2: Continuous IL-7 signaling promotes CD8+ T cell death in vitro.
Figure 3: Continuous IL-7 signaling causes CICD.
Figure 4: IFN-γ signaling is responsible for triggering CICD.
Figure 5: Homeostatic engagement of TCRs prevents IFN-γ induction during in vivo homeostasis.
Figure 6: Effect of in vivo homeostasis on weakly signaled CD5lo CD8+ T cells in normal mice expressing endogenous IL-7Rs.

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Acknowledgements

We thank R. Hodes and N. Taylor for critical reading of the manuscript; S. Sharrow and L. Granger for flow cytometry; and members of the Singer laboratory for discussions. Supported by the Uehara Memorial Foundation (M.Y.K.), the Kanae Foundation (M.Y.K.), and the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research.

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M.Y.K. designed the study, did experiments, analyzed data and contributed to the writing of the manuscript; L.A.P., T.I.G., J.T., A.A., J.-H.P. and X.T. did experiments and analyzed data; A.S. designed the study, analyzed data, and wrote the manuscript.

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Correspondence to Alfred Singer.

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Kimura, M., Pobezinsky, L., Guinter, T. et al. IL-7 signaling must be intermittent, not continuous, during CD8+ T cell homeostasis to promote cell survival instead of cell death. Nat Immunol 14, 143–151 (2013). https://doi.org/10.1038/ni.2494

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