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CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation–mediated apoptosis of effector CD4+ T cells

Nature Immunology volume 8, pages 1353–1362 (2007)Cite this article

Abstract

A key issue in mammalian immunology is how CD4+CD25+Foxp3+ regulatory T cells (Treg cells) suppress immune responses. Here we show that Treg cells induced apoptosis of effector CD4+ T cells in vitro and in vivo in a mouse model of inflammatory bowel disease. Treg cells did not affect the early activation or proliferation of effector CD4+ T cells. Cytokines that signal through the common γ-chain suppressed Treg cell–induced apoptosis. Treg cell–induced effector CD4+ T cell death required the proapoptotic protein Bim, and effector CD4+ T cells incubated with Treg cells showed less activation of the prosurvival kinase Akt and less phosphorylation of the proapoptotic protein Bad. Thus, cytokine deprivation–induced apoptosis is a prominent mechanism by which Treg cells inhibit effector T cell responses.

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Figure 1: Treg cells induce apoptosis of responder T cells in vitro.
Figure 2: Features of Treg cell–induced apoptosis.
Figure 3: Treg cell–induced apoptosis is associated with suppression of cytokine-dependent Akt1 and phosphorylated Bad signaling in responder T cells.
Figure 4: Loss of IL-2 accumulation in cocultures of Treg cells and responder T cell is not due to less IL-2 production by responder T cells.
Figure 5: Cytokine deprivation–induced apoptosis is caused by IL-2 consumption by Treg cells.
Figure 6: Bim-deficient responder T cells are resistant to Treg cell–mediated suppression.
Figure 7: Treg cells ameliorate IBD by inducing apoptosis of colitogenic CD4+CD45RBhi cells.
Figure 8: Treg cells suppress IBD by inducing apoptosis of colitogenic cells in a Bim-dependent way.

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Acknowledgements

We thank R. Germain, R. Schwartz, N. Singh, B. Paul, E. Shevach, R. Siegel, A. Singer, S. Saravanamuthu, D. Simon, H. Su, L. Yu, N. Bidere, C. Trageser, J. Lee, A. Snow and other members of the Lenardo laboratory for suggestions and help; O. Schwartz, M. Czapiga and L. Koo for help in confocal microscopy; and K. Nagashima for assistance in electron microscopy. Spleens from Prf1−/− and gld mice (BALB/c) were from T. Sayers and A. Shanker (National Cancer Institute); Bcl-2 transgenic (CD45.1+) mice were from A. Singer (National Cancer Institute); and spleens from Bim-deficient mice (C57BL/6) were obtained from S. Durum and W. Li (National Cancer Institute). Supported by the intramural research program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; the National Institutes of Health–University of Pennsylvania Immunology graduate partnership program (J.R.); and the National Academy of Sciences/National Research Council (P.P.).

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  1. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Pushpa Pandiyan, Lixin Zheng, Jennifer Reed & Michael J Lenardo

  2. Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Satoru Ishihara

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P.P. designed the study, did experiments and analyzed data with the direction and supervision of M.J.L.; M.J.L. and P.P. wrote the manuscript; L.Z. did ELISAs, analyzed the data and contributed to discussions; S.I. did real-time PCR and analyzed the data; and J.R. helped P.P. in sorting cells for some experiments.

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Correspondence to Michael J Lenardo.

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Pandiyan, P., Zheng, L., Ishihara, S. et al. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation–mediated apoptosis of effector CD4+ T cells. Nat Immunol 8, 1353–1362 (2007). https://doi.org/10.1038/ni1536

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