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Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells

Abstract

Foxp3+ regulatory T (Treg) cells are a crucial immunosuppressive population of CD4+ T cells, yet the homeostatic processes and survival programs that maintain the Treg cell pool are poorly understood. Here we report that peripheral Treg cells markedly alter their proliferative and apoptotic rates to rapidly restore numerical deficit through an interleukin 2–dependent and costimulation-dependent process. By contrast, excess Treg cells are removed by attrition, dependent on the Bim-initiated Bak- and Bax-dependent intrinsic apoptotic pathway. The antiapoptotic proteins Bcl-xL and Bcl-2 were dispensable for survival of Treg cells, whereas Mcl-1 was critical for survival of Treg cells, and the loss of this antiapoptotic protein caused fatal autoimmunity. Together, these data define the active processes by which Treg cells maintain homeostasis via critical survival pathways.

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Figure 1: Homeostatic expansion of Treg cells is driven by increased production of IL-2.
Figure 2: The intrinsic apoptosis pathway is required to restrain Treg cell numbers to homeostatic levels.
Figure 3: Regulatory T cell survival is independent of Bcl-2 and Bcl-xL.
Figure 4: Spontaneous fatal immunopathology after Treg cell–specific deletion of Mcl-1.
Figure 5: Mcl-1 is required for Treg cell survival.
Figure 6: Regulation of Mcl-1 in Treg cells by Bim and IL-2.

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Acknowledgements

We thank P. Fink (University of Washington, Seattle) for providing Rag2–GFP-Tg mice backcrossed to the B6 background, L. Hennighausen (US National Institutes of Health) for providing Bcl2l1fx mice, A. Rudensky (Memorial Sloan-Kettering Cancer Center) for providing Foxp3GFP, Foxp3Cre, Foxp3Thy1.1 and Foxp3DTR mice, G. Kelly and S. Grabow (Walter and Eliza Hall Institute of Medical Research) for CreERT2Mcl1fl and CreERT2Bcl2l1flox mice and Bcl2−/− fetal liver samples, F. Kupresanin, G. Siciliano, G.-F. Dabrowski, K. Humphreys and E. Lanera (Walter and Eliza Hall Institute of Medical Research) for technical assistance, S. Korsmeyer (Harvard Medical School) for BaxflBak1−/− mice, and A. Kallies for critical feedback on the manuscript. This work was supported by grants from the VIB, Marie Curie (TREG to A.L.), European Research Council (IMMUNO to A.L.), Interuniversity Attraction Poles (VII/39 to A.L and P.M.), QSIS (to A.A.F.) and the Australian National Health and Medical Research Council (CDF-1 #637353 to D.H.D.G.). W.P. is funded by Agentschap voor Innovatie door Wetenschap en Technologie. B.C., S.M.S. and S.H.-B. are funded by the Fonds Wetenschappelijk Onderzoek. This work was made possible through Victorian State Government Operational Infrastructure Support and the Australian Government National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme.

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W.P., B.C., A.P., S.M.S., J.B., M.J.H., S.S., D.F., S.H.-B., L.-F.L. and J.D. performed the experiments. D.H., A.S., P.B., R.J.L. and C.T.W. provided key reagents. S.M.S., A.A.F., P.M., J.D., D.H.D.G. and A.L. designed the study. W.P., D.H.D.G. and A.L. wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Daniel H D Gray or Adrian Liston.

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The spouse of A.L. is an employee of UCB Pharma.

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Pierson, W., Cauwe, B., Policheni, A. et al. Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells. Nat Immunol 14, 959–965 (2013). https://doi.org/10.1038/ni.2649

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