Enforced Bcl-2 Expression Inhibits Antigen-mediated Clonal Elimination of Peripheral B Cells in an Antigen Dose–dependent Manner and Promotes Receptor Editing in Autoreactive, Immature B Cells

The mechanisms that establish immune tolerance in immature and mature B cells appear to be distinct. Membrane-bound autoantigen is thought to induce developmental arrest and receptor editing in immature B cells, whereas mature B cells have shortened lifespans when exposed to the same stimulus. In this study, we used Eμ–bcl-2-22 transgenic (Tg) mice to test the prediction that enforced expression of the Bcl-2 apoptotic inhibitor in B cells would rescue mature, but not immature, B cells from tolerance induction. To monitor tolerance to the natural membrane autoantigen H-2Kb, we bred 3–83μδ (anti-Kk,b) Ig Tg mice to H-2b mice or to mice expressing transgene-driven Kb in the periphery. In 3–83μδ/bcl-2 Tg mice, deletion of autoreactive B cells induced by peripheral Kb antigen expression in the liver (MT-Kb Tg) or epithelia (KerIV-Kb Tg), was partly or completely inhibited, respectively. Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose. In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process. These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.

[1]  D. Nemazee,et al.  Self-antigen does not accelerate immature B cell apoptosis, but stimulates receptor editing as a consequence of developmental arrest. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[2]  D. Nemazee,et al.  A functional B cell receptor transgene allows efficient IL-7-independent maturation of B cell precursors. , 1997, Journal of immunology.

[3]  D. Nemazee,et al.  BCR ligation induces receptor editing in IgM+IgD- bone marrow B cells in vitro. , 1997, Immunity.

[4]  F. Alt,et al.  Constitutive Bcl-2 expression during immunoglobulin heavy chain-promoted B cell differentiation expands novel precursor B cells. , 1997, Immunity.

[5]  S. Bondada,et al.  CD5-Mediated Negative Regulation of Antigen Receptor-Induced Growth Signals in B-1 B Cells , 1996, Science.

[6]  M. Jackson,et al.  B cells are exquisitely sensitive to central tolerance and receptor editing induced by ultralow affinity, membrane-bound antigen , 1996, The Journal of experimental medicine.

[7]  N. Klinman The "clonal selection hypothesis" and current concepts of B cell tolerance. , 1996, Immunity.

[8]  K. Rajewsky Clonal selection and learning in the antibody system , 1996, Nature.

[9]  John Calvin Reed A day in the life of the Bcl-2 protein: does the turnover rate of Bcl-2 serve as a biological clock for cellular lifespan regulation? , 1996, Leukemia research.

[10]  F. Finkelman,et al.  bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice , 1996, The Journal of experimental medicine.

[11]  H. Arakawa,et al.  Re-evaluation of the probabilities for productive rearrangements on the κ andλloci , 1996 .

[12]  A. Strasser,et al.  Bcl‐2 and Fas/APO‐1 regulate distinct pathways to lymphocyte apoptosis. , 1995, The EMBO journal.

[13]  G. Núñez,et al.  Bcl-XL displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in transgenic mice , 1995, The Journal of experimental medicine.

[14]  G. Núñez,et al.  Modulation of anti-IgM-induced B cell apoptosis by Bcl-xL and CD40 in WEHI-231 cells. Dissociation from cell cycle arrest and dependence on the avidity of the antibody-IgM receptor interaction. , 1995, Journal of immunology.

[15]  S. Korsmeyer,et al.  Radiation-induced apoptosis is differentially regulated in primary B cells from normal mice and mice with the CBA/N X-linked immunodeficiency. , 1995, Journal of immunology.

[16]  John Calvin Reed,et al.  Expression of Bcl-2, Bcl-x, and Bax after T cell activation and IL-2 withdrawal. , 1995, Journal of immunology.

[17]  Mark M. Davis,et al.  CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+T cells , 1995, Nature.

[18]  T. Behrens,et al.  Bcl-xL rescues WEHI 231 B lymphocytes from oxidant-mediated death following diverse apoptotic stimuli. , 1995, Journal of immunology.

[19]  G. Köhler,et al.  Transitional B cells are the target of negative selection in the B cell compartment , 1995, The Journal of experimental medicine.

[20]  K. Shokat,et al.  Antigen-induced B-cell death and elimination during germinal-centre immune responses , 1995, Nature.

[21]  Kenneth G. C. Smith,et al.  Soluble antigen can cause enhanced apoptosis of germinal-centre B cells , 1995, Nature.

[22]  C. Croce,et al.  Inactivation of Bcl-2 by phosphorylation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  C. Thompson,et al.  The role of bcl‐xL in CD40‐mediated rescue from anti‐μ‐induced apoptosis in WEHI‐231 B lymphoma cells , 1995, European journal of immunology.

[24]  H. Steller Mechanisms and genes of cellular suicide , 1995, Science.

[25]  C. Thompson,et al.  Apoptosis in the pathogenesis and treatment of disease , 1995, Science.

[26]  M. Cohn,et al.  The proportion of B-cell subsets expressing κ and λ light chains changes following antigenic selection☆ , 1995 .

[27]  F. Finkelman,et al.  Cross-linking of membrane immunoglobulin D, in the absence of T cell help, kills mature B cells in vivo , 1995, The Journal of experimental medicine.

[28]  S. Korsmeyer,et al.  Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell death , 1995, Cell.

[29]  S. Cory Regulation of lymphocyte survival by the bcl-2 gene family. , 1995, Annual review of immunology.

[30]  Z. Oltvai,et al.  Heterodimerization with Bax is required for Bcl-2 to repress cell death. , 1995, Current topics in microbiology and immunology.

[31]  M. Cohn,et al.  The proportion of B-cell subsets expressing kappa and lambda light chains changes following antigenic selection. , 1995, Immunology today.

[32]  L. Turka,et al.  Bcl-2 expression during T-cell development: early loss and late return occur at specific stages of commitment to differentiation and survival. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[33]  C. Thompson,et al.  bcl-XL is the major bcl-x mRNA form expressed during murine development and its product localizes to mitochondria. , 1994, Development.

[34]  J. Cyster,et al.  Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire , 1994, Nature.

[35]  P. Cazenave,et al.  Signaling properties of anti‐immunoglobulin — resistant variants of WEHI‐231 B lymphoma cells , 1994, European journal of immunology.

[36]  A. Strasser,et al.  Insights from transgenic mice regarding the role of bcl-2 in normal and neoplastic lymphoid cells. , 1994, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[37]  S. Korsmeyer,et al.  Bcl-2 protein expression during murine development. , 1994, The American journal of pathology.

[38]  D. Green,et al.  Activation-induced apoptosis in lymphocytes. , 1994, Current opinion in immunology.

[39]  D. Baltimore,et al.  Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. , 1994, Genes & development.

[40]  P. Marrack,et al.  Processing and major histocompatibility complex binding of the MTV7 superantigen. , 1994, Immunity.

[41]  John Calvin Reed,et al.  Role of bcl-2 and IL-5 in the regulation of anti-IgM-induced growth arrest and apoptosis in immature B cell lines. A cooperative regulation model for B cell clonal deletion. , 1994, Journal of immunology.

[42]  I. Behrmann,et al.  Regulation of apoptosis in the immune system. , 1994, Current opinion in immunology.

[43]  A. Strasser,et al.  Bcl-2 expression promotes B- but not T-lymphoid development in scid mice , 1994, Nature.

[44]  L. Ding,et al.  Developmental regulation of the Bcl‐2 protein and susceptibility to cell death in B lymphocytes. , 1994, The EMBO journal.

[45]  G. J. V. Nossal,et al.  Negative selection of lymphocytes , 1994, Cell.

[46]  T. Honjo,et al.  Antigen-receptor cross-linking induces peritoneal B-cell apoptosis in normal but not autoimmunity-prone mice , 1994, Current Biology.

[47]  A. Basten,et al.  Reduced life span of anergic self-reactive B cells in a double- transgenic model , 1994, The Journal of experimental medicine.

[48]  A. Gottschalk,et al.  Physiological cell death in B lymphocytes: I. Differential susceptibility of WEHI-231 sublines to anti-Ig induced physiological cell death and lack of correlation with bcl-2 expression. , 1994, International immunology.

[49]  S. Korsmeyer,et al.  Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair , 1993, Cell.

[50]  T. Honjo,et al.  The bcl-2 gene product inhibits clonal deletion of self-reactive B lymphocytes in the periphery but not in the bone marrow , 1993, The Journal of experimental medicine.

[51]  A. Strasser,et al.  Immature surface Ig+ B cells can continue to rearrange kappa and lambda L chain gene loci , 1993, The Journal of experimental medicine.

[52]  V. Stewart,et al.  Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. , 1993, Science.

[53]  R. Hardy,et al.  The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver , 1993, The Journal of experimental medicine.

[54]  S. Korsmeyer,et al.  Expression of the Bcl-2 protein in murine and human thymocytes and in peripheral T lymphocytes. , 1993, Journal of immunology.

[55]  S. Korsmeyer,et al.  Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death , 1993, Cell.

[56]  C. Thompson,et al.  bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death , 1993, Cell.

[57]  L. Ding,et al.  Programmed cell death by bcl‐2‐dependent and independent mechanisms in B lymphoma cells. , 1993, The EMBO journal.

[58]  S. Camper,et al.  Receptor editing: an approach by autoreactive B cells to escape tolerance , 1993, The Journal of experimental medicine.

[59]  D. Nemazee,et al.  Receptor editing in self-reactive bone marrow B cells , 1993, The Journal of experimental medicine.

[60]  M. Cooke,et al.  Elimination of self-reactive B lymphocytes proceeds in two stages: Arrested development and cell death , 1993, Cell.

[61]  D. Scott Analysis of B cell tolerance in vitro. , 1993, Advances in immunology.

[62]  J C Reed,et al.  Differential effects of Bcl-2 on T and B cells in transgenic mice. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[63]  T. Honjo,et al.  Antigen-induced apoptotic death of Ly-1 B cells responsible for autoimmune disease in transgenic mice , 1992, Nature.

[64]  G. Schönrich,et al.  Distinct mechanisms of extrathymic T cell tolerance due to differential expression of self antigen. , 1992, International immunology.

[65]  G. Morahan,et al.  Peripheral deletion of self-reactive B cells , 1991, Nature.

[66]  C. Goodnow,et al.  Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens , 1991, Nature.

[67]  D. Vaux,et al.  Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[68]  R. Ahmed T-cell tolerance to viruses. , 1991, Current opinion in immunology.

[69]  T. Creighton Characterizing intermediates in protein folding , 1991, Current Biology.

[70]  S. Korsmeyer,et al.  Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population , 1990, Molecular and cellular biology.

[71]  B. Nadel,et al.  Murine lambda gene rearrangements: the stochastic model prevails over the ordered model. , 1990, The EMBO journal.

[72]  D. Nemazee,et al.  Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[73]  B. Bloom,et al.  On the mechanism of human T cell suppression. , 1989, International immunology.

[74]  G. Morahan,et al.  Expression in transgenic mice of class I histocompatibility antigens controlled by the metallothionein promoter. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[75]  S. Korsmeyer,et al.  bcl-2-Immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation , 1989, Cell.

[76]  D. Nemazee,et al.  Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes , 1989, Nature.

[77]  K. Struhl,et al.  Suppressors of Saccharomyces cerevisiae his3 promoter mutations lacking the upstream element , 1985, Molecular and cellular biology.

[78]  B. Hogan,et al.  Effect of cyclic nucleotides on the induction of ornithine decarboxylase in BHK cells by serum and insulin. , 1974, Cell.

[79]  M. Haas Continuous production of radiation leukemia virus in c57bl thymoma tissue culture lines, purification of the leukemogenic virus. , 1974 .

[80]  W. Reed ON THE APPEARANCE OF CERTAIN AMŒBOID BODIES IN THE BLOOD OF VACCINATED MONKEYS (RHOESUS) AND CHILDREN, AND IN THE BLOOD FROM CASES OF VARIOLA , 1897, The Journal of experimental medicine.