[en] Regulatory T cells (Tregs) are crucial for the maintenance of immunological self-tolerance and their absence or dysfunction can lead to autoimmunity. However, the molecular pathways that govern Treg biology remain obscure. In this study, we show that the nuclear factor-κB signalling mediator mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an important novel regulator of both Tregs originating in the thymus ('natural' or nTregs) and Tregs induced to differentiate from naive thymocyte helper (Th) cells in the periphery ('induced' or iTregs). Our examination of mice deficient for MALT1 revealed that these mutants have a reduced number of total Tregs. In young Malt1-/- mice, nTregs are totally absent and iTreg are diminished in the periphery. Interestingly, total Treg numbers increase in older Malt1-/- mice as well as in Malt1-/- mice subjected to experimentally induced inflammation. iTregs isolated from WT and Malt1-/- mice were indistinguishable with respect to their ability to suppress the activities of effector T cells, but Malt1-/- iTregs expressed higher levels of Toll-like receptor (TLR) 2. Treatment of WT and Malt1-/- Th cells in vitro with the TLR2 ligand Pam3Cys strongly enhanced the induction and proliferation of Malt1-/- iTregs. Our data suggest that MALT1 supports nTreg development in the thymus but suppresses iTreg induction in the periphery during inflammation. Our data position MALT1 as a key molecule that contributes to immune tolerance at steady-state while facilitating immune reactivity under stress conditions.
Disciplines :
Immunology & infectious disease
Author, co-author :
Brüstle, A; The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada ; Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics ; The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada ; Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, 29, rue Henri Koch, Esch-sur-Alzette L-4354, Luxembourg
Knobbe-Thomsen, C B; Department of Neuropathology, University of Düsseldorf, Düsseldorf, Germany
Cox, M; The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
Lang, P A; Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany ; Department of Molecular Medicine II, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, Düsseldorf D-40225, Germany
Lang, K S; Department of Immunology, University of Essen, Essen, Germany
Mak, T W; The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada ; Faculty of Medicine, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada
External co-authors :
yes
Language :
English
Title :
MALT1 is an intrinsic regulator of regulatory T cells.
Publication date :
July 2017
Journal title :
Cell Death and Differentiation
ISSN :
1350-9047
eISSN :
1476-5403
Publisher :
Nature Publishing Group, Basingstoke, Hampshire, England
This work was supported by grants by the Canadian Institutes of Health Research (to TWM). DB is supported by the ATTRACT Programme of the National Research Fund Luxembourg (FNR).This study was further supported by the Alexander von Humboldt Foundation (SKA2010) and the German Research Council (LA2558/3-1).
Sakaguchi S, Fukuma K, Kuribayashi K, Masuda T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med 1985; 161: 72-87.
Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 2009; 326: 986-991.
Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 2009; 10: 595-602.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330-336.
Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27: 20-21.
Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001; 27: 68-73.
McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002; 16: 311-323.
Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192: 303-310.
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151-1164.
Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity 2009; 30: 616-625.
Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N et al. Conversion of peripheral CD4 +CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003; 198: 1875-1886.
Zheng SG, Wang JH, Stohl W, Kim KS, Gray JD, Horwitz DA. TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 2006; 176: 3321-3329.
Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 2007; 8: 1353-1362.
Liu G, Zhao Y. Toll-like receptors and immune regulation: their direct and indirect modulation on regulatory CD4+ CD25+ T cells. Immunology 2007; 122: 149-156.
Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 2006; 116: 485-494.
Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 2005; 309: 1380-1384.
Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 2003; 197: 403-411.
Crellin NK, Garcia RV, Hadisfar O, Allan SE, Steiner TS, Levings MK. Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J Immunol 2005; 175: 8051-8059.
Sutmuller RP, Morgan ME, Netea MG, Grauer O, Adema GJ. Toll-like receptors on regulatory T cells: expanding immune regulation. Trends Immunol 2006; 27: 387-393.
Netea MG, Sutmuller R, Hermann C, Van der Graaf CA, Van der Meer JW, van Krieken JH et al. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J Immunol 2004; 172: 3712-3718.
Thome M. Multifunctional roles for MALT1 in T-cell activation. Nat Rev Immunol 2008; 8: 495-500.
Rebeaud F, Hailfinger S, Posevitz-Fejfar A, Tapernoux M, Moser R, Rueda D et al. The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat Immunol 2008; 9: 272-281.
Uehata T, Iwasaki H, Vandenbon A, Matsushita K, Hernandez-Cuellar E, Kuniyoshi K et al. Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation. Cell 2013; 153: 1036-1049.
Jeltsch KM, Hu D, Brenner S, Zoller J, Heinz GA, Nagel D et al. Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation. Nat Immunol 2014; 15: 1079-1089.
Ruland J, Duncan GS, Wakeham A, Mak TW. Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 2003; 19: 749-758.
Brustle A, Brenner D, Knobbe CB, Lang PA, Virtanen C, Hershenfield BM et al. The NFkappaB regulator MALT1 determines the encephalitogenic potential of Th17 cells. J Clin Invest 2012; 122: 4698-4709.
Mc Guire C, Wieghofer P, Elton L, Muylaert D, Prinz M, Beyaert R et al. Paracaspase MALT1 deficiency protects mice from autoimmune-mediated demyelination. J Immunol 2013; 190: 2896-2903.
Sato S, Sanjo H, Tsujimura T, Ninomiya-Tsuji J, Yamamoto M, Kawai T et al. TAK1 is indispensable for development of T cells and prevention of colitis by the generation of regulatory T cells. Int Immunol 2006; 18: 1405-1411.
Schmidt-Supprian M, Tian J, Grant EP, Pasparakis M, Maehr R, Ovaa H et al. Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-kappaB activation. Proc Natl Acad Sci USA 2004; 101: 4566-4571.
Wan YY, Chi H, Xie M, Schneider MD, Flavell RA. The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nat Immunol 2006; 7: 851-858.
Molinero LL, Yang J, Gajewski T, Abraham C, Farrar MA, Alegre ML. CARMA1 controls an early checkpoint in the thymic development of FoxP3+ regulatory T cells. J Immunol 2009; 182: 6736-6743.
Barnes MJ, Krebs P, Harris N, Eidenschenk C, Gonzalez-Quintial R, Arnold CN et al. Commitment to the regulatory T cell lineage requires CARMA1 in the thymus but not in the periphery. PLoS Biol 2009; 7: e51.
Fu S, Yopp AC, Mao X, Chen D, Zhang N, Chen D et al. CD4+ CD25+ CD62+ T-regulatory cell subset has optimal suppressive and proliferative potential. Am J Transplant 2004; 4: 65-78.
Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 2010; 184: 3433-3441.
Sutmuller R, Garritsen A, Adema GJ. Regulatory T cells and toll-like receptors: regulating the regulators. Ann Rheum Dis 2007; 66: iii91-iii95.
Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, Radolf JD et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 1999; 285: 736-739.
Venken K, Hellings N, Liblau R, Stinissen P. Disturbed regulatory T cell homeostasis in multiple sclerosis. Trends Mol Med 2010; 16: 58-68.
Shafiani S, Tucker-Heard G, Kariyone A, Takatsu K, Urdahl KB. Pathogen-specific regulatory T cells delay the arrival of effector T cells in the lung during early tuberculosis. J Exp Med 2010; 207: 1409-1420.
Brenner D, Brustle A, Lin GH, Lang PA, Duncan GS, Knobbe-Thomsen CB et al. Toso controls encephalitogenic immune responses by dendritic cells and regulatory T cells. Proc Natl Acad Sci USA 2014; 111: 1060-1065.
Bornancin F, Renner F, Touil R, Sic H, Kolb Y, Touil-Allaoui I et al. Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation. J Immunol 2015; 194: 3723-3734.
Gewies A, Gorka O, Bergmann H, Pechloff K, Petermann F, Jeltsch KM et al. Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation. Cell Rep 2014; 9: 1292-1305.
Jaworski M, Marsland BJ, Gehrig J, Held W, Favre S, Luther SA et al. Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity. EMBO J 2014; 33: 2765-2781.
Gregg R, Smith CM, Clark FJ, Dunnion D, Khan N, Chakraverty R et al. The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age. Clin Exp Immunol 2005; 140: 540-546.
Jeltsch KM, Hu D, Brenner S, Zoller J, Heinz GA, Nagel D et al. Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation. Nat Immunol 2014; 15: 1079-1089.
Watanabe T, Asano N, Murray PJ, Ozato K, Tailor P, Fuss IJ et al. Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J Clin Invest 2008; 118: 545-559.
Lin Y, Lee H, Berg AH, Lisanti MP, Shapiro L, Scherer PE. The lipopolysaccharide-activated toll-like receptor (TLR)-4 induces synthesis of the closely related receptor TLR-2 in adipocytes. J Biol Chem 2000; 275: 24255-24263.
Kingeter LM, Schaefer BC. Loss of protein kinase C theta, Bcl10, or Malt1 selectively impairs proliferation and NF-kappa B activation in the CD4+ T cell subset. J Immunol 2008; 181: 6244-6254.
Ruefli-Brasse AA, French DM, Dixit VM. Regulation of NF-kappaB-dependent lymphocyte activation and development by paracaspase. Science 2003; 302: 1581-1584.
Hara H, Wada T, Bakal C, Kozieradzki I, Suzuki S, Suzuki N et al. The MAGUK family protein CARD11 is essential for lymphocyte activation. Immunity 2003; 18: 763-775.
Mc Guire C, Elton L, Wieghofer P, Staal J, Voet S, Demeyer A et al. Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis. J Neuroinflammation 2014; 11: 124.
Gewies A, Gorka O, Bergmann H, Pechloff K, Petermann F, Jeltsch KM et al. Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation. Cell Rep 2014; 9: 1292-1305.
