Abstract
Members of the Bcl-2 family have critical roles in regulating tissue homeostasis by modulating apoptosis. Anti-apoptotic molecules physically interact and restrain pro-apoptotic family members preventing the induction of cell death. However, the specificity of the functional interactions between pro- and anti-apoptotic Bcl-2 family members remains unclear. The pro-apoptotic Bcl-2 family member Bcl-2 interacting mediator of death (Bim) has a critical role in promoting the death of activated, effector T cells following viral infections. Although Bcl-2 is an important Bim antagonist in effector T cells, and Bcl-xL is not required for effector T-cell survival, the roles of other anti-apoptotic Bcl-2 family members remain unclear. Here, we investigated the role of myeloid cell leukemia sequence 1 (Mcl-1) in regulating effector T-cell responses in vivo. We found, at the peak of the response to lymphocytic choriomeningitis virus (LCMV) infection, that Mcl-1 expression was increased in activated CD4+ and CD8+ T cells. Retroviral overexpression of Mcl-1-protected activated T cells from death, whereas deletion of Mcl-1 during the course of infection led to a massive loss of LCMV-specific CD4+ and CD8+ T cells. Interestingly, the co-deletion of Bim failed to prevent the loss of Mcl-1-deficient T cells. Furthermore, lck-driven overexpression of a Bcl-xL transgene only partially rescued Mcl-1-deficient effector T cells suggesting a lack of redundancy between the family members. In contrast, additional loss of Bax and Bak completely rescued Mcl-1-deficient effector T-cell number and function, without enhancing T-cell proliferation. These data suggest that Mcl-1 is critical for promoting effector T-cell responses, but does so by combating pro-apoptotic molecules beyond Bim.
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Abbreviations
- Bim:
-
Bcl-2-interacting mediator of death
- BM:
-
bone marrow
- LCMV:
-
lymphocytic choriomeningitis virus
- Mcl-1:
-
myeloid cell leukemia sequence 1
- p.f.u.:
-
plaque forming units
- SEB:
-
staphylococcal enterotoxin B
References
Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999; 286: 1735–1738.
Rathmell JC, Lindsten T, Zong WX, Cinalli RM, Thompson CB . Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nat Immunol 2002; 3: 932–939.
Nakayama K, Nakayama K, Negishi I, Kuida K, Shinkai Y, Louie MC et al. Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. Science 1993; 261: 1584–1588.
Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ . Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 1993; 75: 229–240.
Opferman JT, Iwasaki H, Ong CC, Suh H, Mizuno S, Akashi K et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 2005; 307: 1101–1104.
Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ . Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 2003; 426: 671–676.
Kurtulus S, Tripathi P, Opferman JT, Hildeman DA . Contracting the 'mus cells'--does down-sizing suit us for diving into the memory pool? Immunol Rev 2010; 236: 54–67.
D’Cruz LM, Rubinstein MP, Goldrath AW . Surviving the crash: transitioning from effector to memory CD8+ T cell. Semin Immunol 2009; 21: 92–98.
Grayson JM, Weant AE, Holbrook BC, Hildeman D . Role of Bim in Regulating CD8+ T-cell responses during chronic viral infection. J Virol 2006; 80: 8627–8638.
Hildeman DA, Zhu Y, Mitchell TC, Bouillet P, Strasser A, Kappler J et al. Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity 2002; 16: 759–767.
Prlic M, Bevan MJ . Exploring regulatory mechanisms of CD8+ T cell contraction. Proc Natl Acad Sci USA 2008; 105: 16689–16694.
Wojciechowski S, Jordan MB, Zhu Y, White J, Zajac AJ, Hildeman DA . Bim mediates apoptosis of CD127(lo) effector T cells and limits T cell memory. Eur J Immunol 2006; 36: 1694–1706.
Kurtulus S, Tripathi P, Moreno-Fernandez ME, Sholl A, Katz JD, Grimes HL et al. Bcl-2 allows effector and memory CD8+ T cells to tolerate higher expression of Bim. J Immunol 2011; 186: 5729–5737.
Reckling S, Divanovic S, Karp CL, Wojciechowski S, Belkaid Y, Hildeman D . Proapoptotic Bcl-2 family member Bim promotes persistent infection and limits protective immunity. Infect Immun 2008; 76: 1179–1185.
Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R . Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol 2003; 4: 1191–1198.
Mitchell T, Kappler J, Marrack P . Bystander virus infection prolongs activated T cell survival. J Immunol 1999; 162: 4527–4535.
Zhang N, He YW . The antiapoptotic protein Bcl-xL is dispensable for the development of effector and memory T lymphocytes. J Immunol 2005; 174: 6967–6973.
Tripathi P, Kurtulus S, Wojciechowski S, Sholl A, Hoebe K, Morris SC et al. STAT5 is critical to maintain effector CD8+ T cell responses. J Immunol 2010; 185: 2116–2124.
Hildeman D, Jorgensen T, Kappler J, Marrack P . Apoptosis and the homeostatic control of immune responses. Curr Opin Immunol 2007; 19: 516–521.
Dunkle A, Dzhagalov I, He YW . Cytokine-dependent and cytokine-independent roles for Mcl-1: genetic evidence for multiple mechanisms by which Mcl-1 promotes survival in primary T lymphocytes. Cell Death Dis 2011; 2: e214.
Wojciechowski S, Tripathi P, Bourdeau T, Acero L, Grimes HL, Katz JD et al. Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis. J Exp Med 2007; 204: 1665–1675.
Boise LH, Minn AJ, Noel PJ, June CH, Accavitti MA, Lindsten T et al. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity 1995; 3: 87–98.
Hildeman DA, Mitchell T, Aronow B, Wojciechowski S, Kappler J, Marrack P . Control of Bcl-2 expression by reactive oxygen species. Proc Natl Acad Sci USA 2003; 100: 15035–15040.
Dzhagalov I, Dunkle A, He YW . The anti-apoptotic Bcl-2 family member Mcl-1 promotes T lymphocyte survival at multiple stages. J Immunol 2008; 181: 521–528.
Rinkenberger JL, Horning S, Klocke B, Roth K, Korsmeyer SJ . Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev 2000; 14: 23–27.
Takeuchi O, Fisher J, Suh H, Harada H, Malynn BA, Korsmeyer SJ . Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease. Proc Natl Acad Sci USA 2005; 102: 11272–11277.
Chougnet CA, Tripathi P, Lages CS, Raynor J, Sholl A, Fink P et al. A major role for Bim in regulatory T cell homeostasis. J Immunol 2011; 186: 156–163.
Perciavalle RM, Stewart DP, Koss B, Lynch J, Milasta S, Bathina M et al. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat Cell Biol 2012; 14: 575–583.
Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 2005; 17: 393–403.
Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435: 677–681.
Han J, Goldstein LA, Gastman BR, Froelich CJ, Yin XM, Rabinowich H . Degradation of Mcl-1 by granzyme B: implications for Bim-mediated mitochondrial apoptotic events. J Biol Chem 2004; 279: 22020–22029.
Jamil S, Wang SW, Bondy L, Mojtabavi S, Duronio V . Prevention of cytokine withdrawal-induced apoptosis by Mcl-1 requires interaction between Mcl-1 and Bim. Biochem Cell Biol 2010; 88: 809–818.
Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000; 14: 2060–2071.
Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 2005; 19: 1294–1305.
Zhong Q, Gao W, Du F, Wang X . Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 2005; 121: 1085–1095.
Sengupta S, Jayaraman P, Chilton PM, Casella CR, Mitchell TC . Unrestrained glycogen synthase kinase-3 beta activity leads to activated T cell death and can be inhibited by natural adjuvant. J Immunol 2007; 178: 6083–6091.
Stewart DP, Koss B, Bathina M, Perciavalle RM, Bisanz K, Opferman JT . Ubiquitin-independent degradation of antiapoptotic MCL-1. Mol Cell Biol 2010; 30: 3099–3110.
Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10: 375–388.
van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006; 10: 389–399.
Bardwell PD, Gu J, McCarthy D, Wallace C, Bryant S, Goess C et al. The Bcl-2 family antagonist ABT-737 significantly inhibits multiple animal models of autoimmunity. J Immunol 2009; 182: 7482–7489.
Carrington EM, Vikstrom IB, Light A, Sutherland RM, Londrigan SL, Mason KD et al. BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs. Proc Natl Acad Sci USA 2010; 107: 10967–10971.
Fenton RG, Marrack P, Kappler JW, Kanagawa O, Seidman JG . Isotypic exclusion of gamma delta T cell receptors in transgenic mice bearing a rearranged beta-chain gene. Science 1988; 241: 1089–1092.
Hildeman D, Yanez D, Pederson K, Havighurst T, Muller D . Vaccination against persistent viral infection exacerbates CD4+ T-cell-mediated immunopathological disease. J Virol 1997; 71: 9672–9678.
Mitchell TC, Hildeman D, Kedl RM, Teague TK, Schaefer BC, White J et al. Immunological adjuvants promote activated T cell survival via induction of Bcl-3. Nat Immunol 2001; 2: 397–402.
Crawford F, Kozono H, White J, Marrack P, Kappler J . Detection of antigen-specific T cells with multivalent soluble class II MHC covalent peptide complexes. Immunity 1998; 8: 675–682.
Rees W, Bender J, Teague TK, Kedl RM, Crawford F, Marrack P et al. An inverse relationship between T cell receptor affinity and antigen dose during CD4(+) T cell responses in vivo and in vitro. Proc Natl Acad Sci USA 1999; 96: 9781–9786.
Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 1996; 274: 94–96.
Fuller MJ, Zajac AJ . Ablation of CD8 and CD4 T cell responses by high viral loads. J Immunol 2003; 170: 477–486.
Acknowledgements
We thank the Hildeman and Opferman labs for helpful suggestions and comments. This work was supported by Public Health Service Grants AI057753 and DK081175 (to DAH) and HL102175, the American Cancer Society 119130-RSG-10-255-01-LIB, a Cancer Center Support Grant P30CA021765, and the American Lebanese Syrian Associated Charities of St. Judes Children’s Research Hospital (to JTO).
Author Contributions
JTO and DAH designed the research; PT and BK performed the research; DAH, JTO, BK, and PT analyzed and interpreted the data; PT performed the statistical analysis; and JTO and DAH wrote the manuscript.
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Tripathi, P., Koss, B., Opferman, J. et al. Mcl-1 antagonizes Bax/Bak to promote effector CD4+ and CD8+ T-cell responses. Cell Death Differ 20, 998–1007 (2013). https://doi.org/10.1038/cdd.2013.25
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DOI: https://doi.org/10.1038/cdd.2013.25
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