Skip to main content
SpringerLink
Log in

Bcl-x and the regulation of survival in the immune system

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

A variety of experimental models indicate that programmed cell death, or apoptosis, of lymphocytes is a key mechanism in the homeostatic regulation of immunity. Apoptosis is important in early B-and T-cell development to delete cells with nonfunctional antigen receptors, and is also critical for censoring self-reactive cells at the immature lymphocyte stage and at various stages after lymphocytes reach maturity. In this article we focus on the role of the apoptosis regulatory gene bcl-x in controlling survival during lymphocyte development and following B-and T-cell activation. Interesting parallels are observed for bcl-x expression between the B-and T-lineages. The available data also indicate that bcl-x and bcl-2 are expressed in reciprocal patterns during the lifespan of a lymphocyte, suggesting unique regulatory roles for these two survival proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Cohen JJ, Duke RC, Fadok VA, Sellins KS: Apoptosis and programmed cell death in immunity. Ann Rev Immunol 1992; 10:267–293.

    Article  CAS  Google Scholar 

  2. King LB, Ashwell JD: Signaling for death of lymphoid cells. Curr Opin Immunol 1993;5:368–373.

    Article  PubMed  CAS  Google Scholar 

  3. Schwartz LM, Osborne BA: Programmed cell death, apoptosis and killer genes. Immunology Today 1993; 14:582–590.

    Article  PubMed  CAS  Google Scholar 

  4. Nossal GJV:Negative selection of lymphocytes. Cell 1994;76:229–239.

    Article  PubMed  CAS  Google Scholar 

  5. Krammer PH, Behrmann I, Daniel P, Dhein J, Debatin K-M: Regulation of apoptosis in the immune system. Curr Opinion Immunol 1994;6:279–289.

    Article  CAS  Google Scholar 

  6. Green DR, Scott DW: Activationinduced apoptosis in lymphocytes. Curr Opinion Immunol 1994;6: 476–487.

    Article  CAS  Google Scholar 

  7. Nagata S, Golstein P: The Fas death factor. Science 1995;267: 1449–1456.

    Article  PubMed  CAS  Google Scholar 

  8. Sprent J: T and B memory cells. Cell 1994;76:315–322.

    Article  PubMed  CAS  Google Scholar 

  9. Lenardo MJ: Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature 1991;353:858–861.

    Article  PubMed  CAS  Google Scholar 

  10. Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S: The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 1991;66:233–243.

    Article  PubMed  CAS  Google Scholar 

  11. Oehm A, Behrmann I, Falk W, Pawlita M, Maier G, Klas C, Li WM, Richards S, Dhein J, Trauth BC, et al.: Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen. J Biol Chem 1992;267: 10,709–10,715.

    CAS  Google Scholar 

  12. Shi Y, Glynn JM, Guilbert LJ, Cotter TG, Bissonnette RP, Green DR: Role for c-Myc in activationinduced apoptotic cell death in T cell hybridomas. Science 1992; 257:212–214.

    Article  PubMed  CAS  Google Scholar 

  13. Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH: Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 1993;362:849–852.

    Article  PubMed  CAS  Google Scholar 

  14. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T: p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 1993;362:847–849.

    Article  PubMed  CAS  Google Scholar 

  15. Woronicz JD, Calnan B, Ngo V, Winoto A: Requirement for the orphan steroid receptor nur77 in apoptosis of T-cell hybridomas. Nature 1994;367:277–281.

    Article  PubMed  CAS  Google Scholar 

  16. Liu Z-G, Smith SW, McLaughlin KA, Schwartz LM, Osborne BA: Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediateearly gene nur77. Nature 1994; 367:281–284.

    Article  PubMed  CAS  Google Scholar 

  17. Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM: Cloning of the chromosome breakpoint of neoplastic B cells with the t(14:18) chromosome translocation. Science 1984;226:1097–1099.

    Article  PubMed  CAS  Google Scholar 

  18. Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL, Korsmeyer SJ: Cloning the chromosomalbreakpointoft(14:18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985;41:889–906.

    Article  Google Scholar 

  19. Cleary ML, Sklar J: Nucleotide sequence of a t(14:18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci USA 1985;82:7439–7443.

    Article  PubMed  CAS  Google Scholar 

  20. Korsmeyer SJ: Bcl-2:an antidote to programmed cell death. Cancer Surv 1992;15:105–118.

    PubMed  CAS  Google Scholar 

  21. Reed JC: Bcl-2 and the regulation of programmed cell death. J Cell Biol 1994;124:1–6.

    Article  PubMed  CAS  Google Scholar 

  22. Reed JC, Miyashita T, Cuddy M, Cho D: Regulation of p26-bcl-2 protein levels in human peripheral blood lymphocytes. Lab Invest 1992;67:443–449.

    PubMed  CAS  Google Scholar 

  23. Veis DJ, Sentman CL, Bach EA, Korsmeyer SJ: Expression of the Bcl-2 protein in murine and human thymocytes and in peripheral T lymphocytes. J Immunol 1993; 151:2546–2554.

    PubMed  CAS  Google Scholar 

  24. Merino R, Ding L, Veis DJ, Korsmeyer SJ, Nunez G: Developmental regulation of the Bcl-2 protein and susceptibility to cell death in B lymphocytes. EMBO J 1994; 13:683–691.

    PubMed  CAS  Google Scholar 

  25. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ: Bcl-2 deficient mice demonstrate fulminant Iymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 1993;75:229–240.

    Article  PubMed  CAS  Google Scholar 

  26. Nakayama KI, Nakayama K, Negishi I, Kuida K, Shinkai Y, Louie MC, Fields LE, Lucas PJ, Stewart V, Alt FW, Loh DY: Disappearance of the lymphoid system in bcl-2 homozygous mutant chimeric mice. Science 1993;261: 1584–1588.

    Article  PubMed  CAS  Google Scholar 

  27. Nakayama K-I, Nakayama K, Dustin LB, Loh DY: T-B cell interaction inhibits spontaneous apoptosis of mature lymphocytes in bcl-2 deficient mice. J Exp Med 1995;182:1101–1109.

    Article  PubMed  CAS  Google Scholar 

  28. Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW: MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl Acad Sci USA 1993;90: 3516–3520.

    Article  PubMed  CAS  Google Scholar 

  29. Oltvai ZN, Milliman CL, Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74:609–619.

    Article  PubMed  CAS  Google Scholar 

  30. Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB: Bcl-x, a bcl-2 related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993;74:597–608.

    Article  PubMed  CAS  Google Scholar 

  31. Lin EY, Orlofsky A, Berger MS, Prystowsky MB: Characterization of A1, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2. J Immunol 1993;151:1979–1988.

    PubMed  CAS  Google Scholar 

  32. Yang E,ZhaJ, Jockei J, Boise LH, Thompson CB, Korsmeyer SJ: Bad, a heterodimeric partner for bcl-xL and bcl-2, displaces bax and promotes cell death. Cell 1995;80:285–291.

    Article  PubMed  CAS  Google Scholar 

  33. Kiefer MC, Brauer MJ, Powers VC, Wu JJ, Umansky SR, Tomei LD, Barr PJ: Modulation of apoptosis by the widely distributed bcl-2 homologue bak. Nature 1995;374:736–739.

    Article  PubMed  CAS  Google Scholar 

  34. Fang W, Rivard JJ, Mueller DL, Behrens TW: Cloning and molecular characterization of mouse bcl-x in B and T lymphocytes. J Immunol 1994;153:4388–4398.

    PubMed  CAS  Google Scholar 

  35. Gonzalez-Garcia M, Perez-Ballestero R, Ding L, Duan L, Boise LH, Thompson CB, Nunez G: Bcl-xL is the major bcl-x mRNA form expressed during murine development and its product localizes to mitochondria. Development, 1994; 120:3033–3042.

    PubMed  CAS  Google Scholar 

  36. Jaattela M, Benedict M, Tewari M, Shayman JA, Dixit VM: Bcl-x and bcl-2 inhibit TNF andFas-induced apoptosis and activation of phospholipase A(2) in breast carcinoma cells. Oncogene 1995; 10: 2297–2305.

    PubMed  CAS  Google Scholar 

  37. Minn AJ, Rudin CM, Boise LH, Thompson CB: Expression of bclxL can confer a multidrug resistance phenotype. Blood 1995;86: 1903–1910.

    PubMed  CAS  Google Scholar 

  38. Choi M, Boise LH, Gottschalk AR, Quintans J, Thompson CB, Klaus GGB: The role of bcl-x(L) in CD40-mediated rescue from anti-mu-induced apoptosis in WEHI-231 B lymphoma cells. Eur J Immunol 1995;25:1352–1357.

    Article  PubMed  CAS  Google Scholar 

  39. Dole MG, Jasty R, Cooper MJ, Thompson CB, Nunez G, Castle VP: Bcl-x(l) is expressed in neuroblastoma cells and modulates chemotherapy-induced apoptosis. Cancer Res 1995;55:2576–2582.

    PubMed  CAS  Google Scholar 

  40. Fang W, Rivard JJ, Ganser JA, LeBien TW, Nath KA, Mueller DL, Behrens TW: Bcl-xL rescues WEHI 231 B lymphocytes from oxidant-mediated death following diverse apoptotic stimuli. J Immunol 1995;155:66–75.

    PubMed  CAS  Google Scholar 

  41. Motoyama N, Wang F, Roth KA, Sawa H, Nakayama K, Nakayama K, Negishi I, Senju S, Zhang Q, Fujii S, Loh DY: Massive cell death of immature hematopoietic cells and neurons in bcl-x-deficient mice. Science 1995;267: 1506–1510.

    Article  PubMed  CAS  Google Scholar 

  42. Minn AJ, Boise LH, Thompson CB: Bcl-xS antaganizes the protective effects of bcl-xl. J Biol Chem 1996;271:6306–6312.

    Article  PubMed  CAS  Google Scholar 

  43. Evan DL, Mansel RE: Molecular evolution and secondary structural conservation in the B-cell lymphoma and leukemia 2 (bcl-2) family of proto-oncogene products. J Mol Evol 1995;41:775–783.

    Google Scholar 

  44. Chen-Levy Z, Cleary ML: Membrane topology of the bcl-2 protooncogenic protein demonstrated in vitro. J Biol Chem 1990;265: 4929–4933.

    PubMed  CAS  Google Scholar 

  45. Nguyen M, Millar DG, Yong VW, Korsmeyer SJ, Shore GC: Targeting of bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J Biol Chem 1993;268:25,265–25,268.

    CAS  Google Scholar 

  46. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ: Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990. 348:334–336.

    Article  PubMed  CAS  Google Scholar 

  47. Jacobson MD, JF Burne, MP King, T Miyashita, JC Reed, and MC Raff, Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA Nature 1993;361:365–369.

    Article  PubMed  CAS  Google Scholar 

  48. Lithgow T, van Driel R, Bertram JF, Strasser A: The protein product of the oncogene bcl-2 is a component of the nuclear envelope, the endoplasmic reticulum, and the outer mitochondrial membrane. Cell Growth Different 1994;5:411–417.

    CAS  Google Scholar 

  49. Scott DW, Tuttle J, Livnat D, Haynes W, Cogswell J, Keng P: Lymphoma models for B-cell activation and tolerance. II Growth inhibition by anti-mu of WEHI231 and the selection of properties of resistantmutants. Cell Immunol 1985;93:124–132.

    Article  PubMed  CAS  Google Scholar 

  50. Benhamou LE, Cazenave PA, Sarthou P: Anti-immunoglobulins induce death by apoptosis in WEHI-231 B lymphoma cells. Eur J Immunol 1990;20:1405–1407.

    Article  PubMed  CAS  Google Scholar 

  51. Hasbold J, GG Klaus: Antiimmunoglobulin antibodies induce apoptosis in immature B cell lymphomas. Eur J Immunol 1990;20: 1685–1690.

    Article  PubMed  CAS  Google Scholar 

  52. Merino R, Grillot DAM, Simonian PL, Muthukkumar S, Fanslow WC, Bondada S, Nunez G: Modulation of anti-IgM-induced B cell apoptosis by bcl-xL and CD40 in WEHI-231 cells. J Immunol 1995; 155:3830–3838.

    PubMed  CAS  Google Scholar 

  53. Ishida T, Kobayashi N, Tojo T, Ishida S, Yamamoto T, Inoue J: CD40 signaling-mediated induction of bcl-xL, Cdk4, and Cdk6. J Immunol 1995;155:5527–5535.

    PubMed  CAS  Google Scholar 

  54. Grillot DAM, Merino R, Pena JC, Fanslow WC, Finkelman FD, Thompson CB, Nunez G: Bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice. J Exp Med 1996;183:381–391.

    Article  PubMed  CAS  Google Scholar 

  55. Choi MSK,HolmanM, Atkins CJ, Klaus GGB: Expression of bcl-x during mouse B cell differentiation and following activation by various stimuli. Eur J Immunol 1996;26:676–682.

    Article  PubMed  CAS  Google Scholar 

  56. Fang W, Nath KA, Mackey MF, Noelle RJ, Mueller DL, Behrens TW: CD40 inhibits B cell apoptosis by upregulating bcl-xL expression and blocking oxidant accumulation. Am J Physiol 272 (Cell Physiol): 1997;C950-C956.

    PubMed  CAS  Google Scholar 

  57. Marshall LS, Aruffo A, Ledbetter JA, Noelle RJ: The molecular basis for T cell help in humoral immunity: CD40 and its ligand, gp39. J Clin Immunol 1993; 13: 165–174.

    Article  PubMed  CAS  Google Scholar 

  58. Bancereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, van Kooten C, Liu YJ, Rousset F, Saeland S: The CD40 antigen and its ligand. Annu Rev Immunol 1994;12:881–922.

    Article  Google Scholar 

  59. Fang W, Mueller DL, Pennell CA, Rivard JJ, Li Y-S, Hardy RR, Schlissel M, Behrens TW: Frequent aberrant immunoglobulin gene rearrangements in pro-B cells revealed by a bcl-xL transgene. Immunity 1996;4:291–299.

    Article  PubMed  CAS  Google Scholar 

  60. Hardy RR, Carmack CE, Shinton SA, Kemp JD, Hayakawa K: Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J Exp Med 1991;173:1213–1225.

    Article  PubMed  CAS  Google Scholar 

  61. Krajewski S, Krajewska M, Shabaik A, Wang HG, Irie S, Fong L, Reed JC: Immunohistochemical analysis of in vivo patterns of bcl-x expression. Cancer Res 1994;54: 5501–5507.

    PubMed  CAS  Google Scholar 

  62. Grillot DAM, Merino R, Nunez G: Bcl-xL displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in transgenic mice. J Exp Med 1995;182:1973–1983.

    Article  PubMed  CAS  Google Scholar 

  63. Ma A, Pena JC, Chang B, Margosian E, Davidson L, Alt FW, Thompson CB: Bcl-x regulates survival of double positive thymocytes. Proc Natl Acad Sci USA 1995;92:4763–4767.

    Article  PubMed  CAS  Google Scholar 

  64. Ohta K, Iwai K, Kasahara Y, Taniguchi N, Krajewski S, Reed JC, Miyawaki T: Immunoblot analysis of cellular expression of bcl-2 family proteins, bcl-2, bax, bcl-x and mcl-1, in human peripheral blood and lymphoid tissues. Int Immunol 1995;7:1817–1825.

    Article  PubMed  CAS  Google Scholar 

  65. Gratiot-Deans, J, L Ding, LA Turka, and G Nunez, Bcl-2 protooncogene expression during human T cell development. J Immunol 1993;151:83–91.

    PubMed  CAS  Google Scholar 

  66. Gratiot-Deans J, Merino R, Nunez G, Turka L: Bcl-2 expression during T-cell development: Early loss and late return occur at specific stages of commitment to differentiation and survival. Proc Natl Acad Sci USA 1994;91:10,685–10,689.

    Article  CAS  Google Scholar 

  67. Linette GP, Grusby JJ, Hedrick SM, Hansen TH, Glimcher LH, Korsmeyer SJ: Bcl-2 is upregulated at the CD4+CD8+ stage during positive selection and promotes thymocyte differentiation at several control points. Immunity, 1994;197-205.

  68. Sentman CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ: Bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 1991;67:879–888.

    Article  PubMed  CAS  Google Scholar 

  69. Boise LH, Minn AJ, Noel PJ, June CH, Accavitti MA, Linsten TL, Thompson CB: CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-xL Immunity 1995;3: 87–98.

    Article  PubMed  CAS  Google Scholar 

  70. Mueller DL, Fang W, Behrens TW: Differential regulation of bcl-2 and bcl-x by CD3, CD28, and the IL-2 receptor in cloned CD4+ helper T cells: A model for long-term survival of memory T cells. J Immunol 1996; 156: 1764–1771.

    PubMed  CAS  Google Scholar 

  71. Broome HE, Dargan CM, Krajewski S, Reed JC: Expression of Bcl-2, Bcl-x and Bax after T cell activation and IL-2 withdrawal. J Immunol 1995; 155:2311–2317.

    PubMed  CAS  Google Scholar 

  72. Sperling AI, Auger JA, Ehst BD, Rulifson IC, Thompson CB, Bluestone JA: CD28/B7 interactions deliver a unique signal to naive T cells that regulates cell survival but not early proliferation. J Immunol 1996;157: 3909–3917.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Immunology and Department of Medicine, University of Minnesota Medical School, 515 Delaware St. SE Minneapolis, 55455, Minneapolis, MN

    Timothy W. Behrens & Daniel L. Mueller

Authors
  1. Timothy W. Behrens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel L. Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Timothy W. Behrens.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Behrens, T.W., Mueller, D.L. Bcl-x and the regulation of survival in the immune system. Immunol Res 16, 149–160 (1997). https://doi.org/10.1007/BF02786359

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02786359

Key Words

Search

Navigation