Abstract
Regulatory T (Treg) cells play an essential role in maintaining immune balance across various physiological and pathological conditions. However, the mechanisms underlying Treg homeostasis remain incompletely understood. Here, we report that RIPK1 is crucial for Treg cell survival and homeostasis. We generated mice with Treg cell-specific ablation of Ripk1 and found that these mice developed fatal systemic autoimmunity due to a dramatic reduction in the Treg cell compartment caused by excessive cell death. Unlike conventional T cells, Treg cells with Ripk1 deficiency were only partially rescued from cell death by blocking FADD-dependent apoptosis. However, simultaneous removal of both Fadd and Ripk3 completely restored the homeostasis of Ripk1-deficient Treg cells by blocking two cell death pathways. Thus, our study highlights the critical role of RIPK1 in regulating Treg cell homeostasis by controlling both apoptosis and necroptosis, thereby providing novel insights into the mechanisms of Treg cell homeostasis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N. Regulatory T cells and human disease. Annu Rev Immunol. 2020;38:541–66.
Smigiel KS, Srivastava S, Stolley JM, Campbell DJ. Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation. Immunol Rev. 2014;259:40–59.
Pierson W, Cauwe B, Policheni A, Schlenner SM, Franckaert D, Berges J, et al. Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells. Nat Immunol. 2013;14:959–65.
Liston A, Gray DHD. Homeostatic control of regulatory T cell diversity. Nat Rev Immunol. 2014;14:154–65.
Levine AG, Arvey A, Jin W, Rudensky AY. Continuous requirement for the TCR in regulatory T cell function. Nat Immunol. 2014;15:1070–8.
Huehn J, Siegmund K, Lehmann JC, Siewert C, Haubold U, Feuerer M, et al. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J Exp Med. 2004;199:303–13.
Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998;281:1680–3.
Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M, Minna J, et al. Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell. 2007;12:445–56.
Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. Cell. 2008;133:693–703.
Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148:213–27.
Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci USA. 2012;109:5322–7.
Dillon CP, Weinlich R, Rodriguez DA, Cripps JG, Quarato G, Gurung P, et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell. 2014;157:1189–202.
Kearney CJ, Cullen SP, Clancy D, Martin SJ. RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis. FEBS J. 2014;281:4921–34.
Dannappel M, Vlantis K, Kumari S, Polykratis A, Kim C, Wachsmuth L, et al. RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature. 2014;513:90–4.
Tan S, Zhao J, Sun Z, Cao S, Niu K, Zhong Y, et al. Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma. Proc Natl Acad Sci USA. 2020;117:14231–42.
Cuchet-Lourenco D, Eletto D, Wu C, Plagnol V, Papapietro O, Curtis J, et al. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science. 2018;361:810–3.
Li Y, Fuhrer M, Bahrami E, Socha P, Klaudel-Dreszler M, Bouzidi A, et al. Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. Proc Natl Acad Sci USA. 2019;116:970–5.
Dowling JP, Cai Y, Bertin J, Gough PJ, Zhang J. Kinase-independent function of RIP1, critical for mature T-cell survival and proliferation. Cell Death Dis. 2016;7:e2379.
Smigiel KS, Richards E, Srivastava S, Thomas KR, Dudda JC, Klonowski KD, et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J Exp Med. 2014;211:121–36.
Luo CT, Liao W, Dadi S, Toure A, Li MO. Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity. Nature. 2016;529:532–6.
Takahashi N, Vereecke L, Bertrand MJ, Duprez L, Berger SB, Divert T, et al. RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis. Nature. 2014;513:95–9.
Roderick JE, Hermance N, Zelic M, Simmons MJ, Polykratis A, Pasparakis M, et al. Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis. Proc Natl Acad Sci USA. 2014;111:14436–41.
Mifflin L, Ofengeim D, Yuan J. Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target. Nat Rev Drug Discov. 2020;19:553–71.
Su H, Bidere N, Zheng L, Cubre A, Sakai K, Dale J, et al. Requirement for caspase-8 in NF-kappaB activation by antigen receptor. Science. 2005;307:1465–8.
Misra RS, Russell JQ, Koenig A, Hinshaw-Makepeace JA, Wen R, Wang D, et al. Caspase-8 and c-FLIPL associate in lipid rafts with NF-kappaB adaptors during T cell activation. J Biol Chem. 2007;282:19365–74.
Shan B, Pan H, Najafov A, Yuan J. Necroptosis in development and diseases. Genes Dev. 2018;32:327–40.
Zhang X, Zhang H, Xu C, Li X, Li M, Wu X, et al. Ubiquitination of RIPK1 suppresses programmed cell death by regulating RIPK1 kinase activation during embryogenesis. Nat Commun. 2019;10:4158.
Tang Y, Tu H, Zhang J, Zhao X, Wang Y, Qin J, et al. K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell death during embryogenesis and inflammation. Nat Commun. 2019;10:4157.
Kist M, Kőműves LG, Goncharov T, Dugger DL, Yu C, Roose-Girma M, et al. Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death. Cell Death Differ. 2021;28:985–1000.
Li W, Shan B, Zou C, Wang H, Zhang MM, Zhu H, et al. Nuclear RIPK1 promotes chromatin remodeling to mediate inflammatory response. Cell Res. 2022;32:621–37.
Bilate AM, Lafaille JJ. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol. 2012;30:733–58.
Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature. 2011;478:250–4.
Barbi J, Pardoll D, Pan F. Treg functional stability and its responsiveness to the microenvironment. Immunol Rev. 2014;259:115–39.
Zhang Y, Rosenberg S, Wang H, Imtiyaz HZ, Hou YJ, Zhang J. Conditional Fas-associated death domain protein (FADD): GFP knockout mice reveal FADD is dispensable in thymic development but essential in peripheral T cell homeostasis. J Immunol. 2005;175:3033–44.
Collison LW, Vignali DA. In vitro Treg suppression assays. Methods Mol Biol. 2011;707:21–37.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
Acknowledgements
This work was supported by the following grants: National Key Research and Development Program of China (2021YFA1301402), Shanghai Municipal Science and Technology Major Project (ZD2021CY001), National Key Research and Development Program of China (2021YFE0200900; 2022YFA0807300), National Natural Science Foundation of China (82101833, 82073901), Three-year Action Plan for Shanghai TCM Development and Inheritance Program [ZY(2021-2023)-0103], Top-level Clinical Discipline Project of Shanghai Pudong District (grant/award number: PWYgf 2021-01), and Training Plan for Discipline Leaders of Shanghai Pudong New Area Health Commission (grant/award number: PWRd2020-09).
Author information
Authors and Affiliations
Contributions
HZ and HW conceived and supervised the research; XD, LW, YZ, ZY, YC, YS, YZ, HZ and HW contributed to the project design and discussions; XD, LW and YZ conducted the experiments; QL, YZ, WZ, YT, TW and JD helped with the mixed bone marrow chimera experiments and some phenotype analysis; FD and JR assisted with mouse models; PH did the bioinformatics analysis; XD, LW, YZ, ZY, YZ, HZ and HW wrote and edited the manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Deng, X., Wang, L., Zhai, Y. et al. RIPK1 plays a crucial role in maintaining regulatory T-Cell homeostasis by inhibiting both RIPK3- and FADD-mediated cell death. Cell Mol Immunol 21, 80–90 (2024). https://doi.org/10.1038/s41423-023-01113-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41423-023-01113-x
Keywords
This article is cited by
-
Not to be and how not to be: the questions of Tregs controlled by RIPK1
Cellular & Molecular Immunology (2024)