Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Takada, K. & Jameson, S.C. Naive T cell homeostasis: from awareness of space to a sense of place. Nat. Rev. Immunol. 9, 823–832 (2009).

    CAS  PubMed  Google Scholar 

  2. Surh, C.D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008).

    CAS  PubMed  Google Scholar 

  3. Sprent, J. & Surh, C.D. Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat. Immunol. 12, 478–484 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Goldrath, A.W. & Bevan, M.J. Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–262 (1999).

    CAS  Google Scholar 

  5. Seddon, B. & Zamoyska, R. Regulation of peripheral T-cell homeostasis by receptor signalling. Curr. Opin. Immunol. 15, 321–324 (2003).

    CAS  PubMed  Google Scholar 

  6. Schluns, K.S., Kieper, W.C., Jameson, S.C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat. Immunol. 1, 426–432 (2000).

    CAS  PubMed  Google Scholar 

  7. Tan, J.T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl. Acad. Sci. USA 98, 8732–8737 (2001).

    CAS  PubMed  Google Scholar 

  8. Vivien, L., Benoist, C. & Mathis, D. T lymphocytes need IL-7 but not IL-4 or IL-6 to survive in vivo. Int. Immunol. 13, 763–768 (2001).

    CAS  PubMed  Google Scholar 

  9. Mazzucchelli, R. & Durum, S.K. Interleukin-7 receptor expression: intelligent design. Nat. Rev. Immunol. 7, 144–154 (2007).

    CAS  PubMed  Google Scholar 

  10. Jiang, Q. et al. Cell biology of IL-7, a key lymphotrophin. Cytokine Growth Factor Rev. 16, 513–533 (2005).

    CAS  PubMed  Google Scholar 

  11. Rochman, Y., Spolski, R. & Leonard, W.J. New insights into the regulation of T cells by gamma(c) family cytokines. Nat. Rev. Immunol. 9, 480–490 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Wofford, J.A., Wieman, H.L., Jacobs, S.R., Zhao, Y. & Rathmell, J.C. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 111, 2101–2111 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Park, J.H. et al. Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity 21, 289–302 (2004).

    CAS  PubMed  Google Scholar 

  14. Swainson, L. et al. IL-7-induced proliferation of recent thymic emigrants requires activation of the PI3K pathway. Blood 109, 1034–1042 (2007).

    CAS  PubMed  Google Scholar 

  15. Kerdiles, Y.M. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10, 176–184 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Tanchot, C., Lemonnier, F.A., Perarnau, B., Freitas, A.A. & Rocha, B. Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276, 2057–2062 (1997).

    CAS  PubMed  Google Scholar 

  17. Kirberg, J., Berns, A. & von Boehmer, H. Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded molecules. J. Exp. Med. 186, 1269–1275 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Nesic, D. & Vukmanovic, S. MHC class I is required for peripheral accumulation of CD8+ thymic emigrants. J. Immunol. 160, 3705–3712 (1998).

    CAS  PubMed  Google Scholar 

  19. Ernst, B., Lee, D.S., Chang, J.M., Sprent, J. & Surh, C.D. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173–181 (1999).

    CAS  PubMed  Google Scholar 

  20. Markiewicz, M.A., Brown, I. & Gajewski, T.F. Death of peripheral CD8+ T cells in the absence of MHC class I is Fas-dependent and not blocked by Bcl-xL. Eur. J. Immunol. 33, 2917–2926 (2003).

    CAS  PubMed  Google Scholar 

  21. Takada, K. & Jameson, S.C. Self-class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels. J. Exp. Med. 206, 2253–2269 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Cho, J.H., Kim, H.O., Surh, C.D. & Sprent, J. T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis. Immunity 32, 214–226 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Polic, B., Kunkel, D., Scheffold, A. & Rajewsky, K. How alpha beta T cells deal with induced TCR alpha ablation. Proc. Natl. Acad. Sci. USA 98, 8744–8749 (2001).

    CAS  PubMed  Google Scholar 

  24. Park, J.H. et al. 'Coreceptor tuning': cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nat. Immunol. 8, 1049–1059 (2007).

    CAS  PubMed  Google Scholar 

  25. Bream, J.H. et al. A distal region in the interferon-γ gene is a site of epigenetic remodeling and transcriptional regulation by interleukin-2. J. Biol. Chem. 279, 41249–41257 (2004).

    CAS  PubMed  Google Scholar 

  26. Xu, X., Sun, Y.L. & Hoey, T. Cooperative DNA binding and sequence-selective recognition conferred by the STAT amino-terminal domain. Science 273, 794–797 (1996).

    CAS  PubMed  Google Scholar 

  27. Sarafova, S.D. et al. Modulation of coreceptor transcription during positive selection dictates lineage fate independently of TCR/coreceptor specificity. Immunity 23, 75–87 (2005).

    CAS  PubMed  Google Scholar 

  28. Noguchi, M. et al. Functional cleavage of the common cytokine receptor gamma chain (gammac) by calpain. Proc. Natl. Acad. Sci. USA 94, 11534–11539 (1997).

    CAS  PubMed  Google Scholar 

  29. Lee, I.H., Li, W.P., Hisert, K.B. & Ivashkiv, L.B. Inhibition of interleukin 2 signaling and signal transducer and activator of transcription (STAT)5 activation during T cell receptor-mediated feedback inhibition of T cell expansion. J. Exp. Med. 190, 1263–1274 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhu, J. et al. Transient inhibition of interleukin 4 signaling by T cell receptor ligation. J. Exp. Med. 192, 1125–1134 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Erman, B. et al. Coreceptor signal strength regulates positive selection but does not determine CD4/CD8 lineage choice in a physiologic in vivo model. J. Immunol. 177, 6613–6625 (2006).

    CAS  PubMed  Google Scholar 

  32. Badovinac, V.P., Tvinnereim, A.R. & Harty, J.T. Regulation of antigen-specific CD8+ T cell homeostasis by perforin and interferon-γ. Science 290, 1354–1358 (2000).

    CAS  PubMed  Google Scholar 

  33. Lohman, B.L. & Welsh, R.M. Apoptotic regulation of T cells and absence of immune deficiency in virus-infected gamma interferon receptor knockout mice. J. Virol. 72, 7815–7821 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu, Y. & Janeway, C.A. Jr. Interferon γ plays a critical role in induced cell death of effector T cell: a possible third mechanism of self-tolerance. J. Exp. Med. 172, 1735–1739 (1990).

    CAS  PubMed  Google Scholar 

  35. Refaeli, Y., Van Parijs, L., Alexander, S.I. & Abbas, A.K. Interferon γ is required for activation-induced death of T lymphocytes. J. Exp. Med. 196, 999–1005 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Dalton, D.K., Haynes, L., Chu, C.Q., Swain, S.L. & Wittmer, S. Interferon γ eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells. J. Exp. Med. 192, 117–122 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Tomita, Y., Bilim, V., Hara, N., Kasahara, T. & Takahashi, K. Role of IRF-1 and caspase-7 in IFN-γ enhancement of Fas-mediated apoptosis in ACHN renal cell carcinoma cells. Int. J. Cancer 104, 400–408 (2003).

    CAS  PubMed  Google Scholar 

  38. Watanabe, Y., Suzuki, O., Haruyama, T. & Akaike, T. Interferon-γ induces reactive oxygen species and endoplasmic reticulum stress at the hepatic apoptosis. J. Cell. Biochem. 89, 244–253 (2003).

    CAS  PubMed  Google Scholar 

  39. Pyo, C.W., Lee, S.H. & Choi, S.Y. Oxidative stress induces PKR-dependent apoptosis via IFN-γ activation signaling in Jurkat T cells. Biochem. Biophys. Res. Commun. 377, 1001–1006 (2008).

    CAS  PubMed  Google Scholar 

  40. Chang, J.H., Kim, Y.J., Han, S.H. & Kang, C.Y. IFN-γ–STAT1 signal regulates the differentiation of inducible Treg: potential role for ROS-mediated apoptosis. Eur. J. Immunol. 39, 1241–1251 (2009).

    CAS  PubMed  Google Scholar 

  41. Mertsching, E., Burdet, C. & Ceredig, R. IL-7 transgenic mice: analysis of the role of IL-7 in the differentiation of thymocytes in vivo and in vitro. Int. Immunol. 7, 401–414 (1995).

    CAS  PubMed  Google Scholar 

  42. Yu, Q., Erman, B., Park, J.H., Feigenbaum, L. & Singer, A. IL-7 receptor signals inhibit expression of transcription factors TCF-1, LEF-1, and RORgammat: impact on thymocyte development. J. Exp. Med. 200, 797–803 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Alfred Singer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 (PDF 313 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2494

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing