Selection?Does CD40 Ligation Induce B Cell Negative

Binding of CD154 to its receptor, CD40, provides costimulation for mature B cell activation and differentiation in response to Ag receptor signals. In mice, early B cell precursors express CD40, but its function at this stage is unknown. We examined the effects of CD40 ligation during B cell ontogeny in transgenic mice constitutively expressing CD154 on B cells ( (cid:1) EP-CD154). Precursors beyond pro-B cells were absent in adult bone marrow but were increased in the fetal liver. Newborn (cid:1) EP-CD154 mice had largely increased numbers of peripheral B cells, which were CD154 (cid:2) , and that 36 h after birth expressed high surface levels of CD23 and MHC class II, resembling activated mature B cells. Nevertheless, (cid:1) EP-CD154 mice were hypogammaglobulinemic, indicating that the expanded population of apparently activated B cells was nonfunctional. Further analysis revealed that soon after birth, (cid:1) EP-CD154 mice-derived B cells became CD5 (cid:2) /Fas (cid:2) , after which progressively decreased in the periphery in a CD154-CD40-dependent manner. These results indicate that CD40 ligation during B cell ontogeny induces negative selection characterized by either hyporesponsiveness or an arrest in maturation depending on the time of analysis and the anatomic site studied. The Journal of Immunology, 2002, 168: 1042–1049. cell-dependent cell Ag receptor cross-linking, costimulatory molecule costimulatory for T cells of family member by ligation on

[1]  T. Luger,et al.  Overexpression of Cd40 Ligand in Murine Epidermis Results in Chronic Skin Inflammation and Systemic Autoimmunity , 2001, The Journal of experimental medicine.

[2]  G. Zhu,et al.  Progressive Depletion of Peripheral B Lymphocytes in 4-1BB (CD137) Ligand/I-Eα-Transgenic Mice1 , 2001, The Journal of Immunology.

[3]  C. Verfaillie,et al.  A novel in vitro model of early human adult B lymphopoiesis that allows proliferation of pro-B cells and differentiation to mature B lymphocytes , 2000, Leukemia.

[4]  T. Behrens,et al.  Cd5 Maintains Tolerance in Anergic B Cells , 2000, The Journal of experimental medicine.

[5]  J. Banchereau,et al.  CD40‐CD40 ligand , 2000, Journal of leukocyte biology.

[6]  P. Hodgkin,et al.  Switch recombination and germ-line transcription are division-regulated events in B lymphocytes. , 1999, Biochimica et biophysica acta.

[7]  K. Rajewsky,et al.  B Cell Antigen Receptor Specificity and Surface Density Together Determine B-1 versus B-2 Cell Development , 1999, The Journal of experimental medicine.

[8]  O. Witte,et al.  In vitro reconstitution of human B-cell ontogeny: from CD34(+) multipotent progenitors to Ig-secreting cells. , 1998, Blood.

[9]  S. Datta.  Production of pathogenic antibodies: Cognate interactions between autoimmune T and B cells , 1998, Lupus.

[10]  K. Davies,et al.  Peripheral blood lymphocytes in SLE--hyperexpression of CD154 on T and B lymphocytes and increased number of double negative T cells. , 1998, Journal of autoimmunity.

[11]  E. Krebs,et al.  p38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes. , 1998, Journal of immunology.

[12]  R. Berland,et al.  An NFAT-dependent enhancer is necessary for anti-IgM-mediated induction of murine CD5 expression in primary splenic B cells. , 1998, Journal of immunology.

[13]  I. Weissman,et al.  Arrest of B lymphocyte terminal differentiation by CD40 signaling: mechanism for lack of antibody-secreting cells in germinal centers. , 1998, Immunity.

[14]  R. Noelle,et al.  Evidence for a continued requirement for CD40/CD40 ligand (CD154) interactions in the progression of LP-BM5 retrovirus-induced murine AIDS. , 1998, Virology.

[15]  D. Gray,et al.  Regulation of cytoplasmic, surface and soluble forms of CD40 ligand in mouse B cells , 1998, European journal of immunology.

[16]  S. Hirohata.  The role of CD40-CD40 ligand interactions in suppression of human B cell responsiveness by CD4+ T cells. , 1997, Cellular immunology.

[17]  K. Gilbert,et al.  CD40 ligand expressed on B cells in the BXSB mouse model of systemic lupus erythematosus. , 1997, Journal of immunology.

[18]  L. de Leij,et al.  Effect of B‐cell receptor engagement on CD40‐stimulated B cells , 1997, Immunology.

[19]  V. Kindler,et al.  Memory, but not naive, peripheral blood B lymphocytes differentiate into Ig-secreting cells after CD40 ligation and costimulation with IL-4 and the differentiation factors IL-2, IL-10, and IL-3. , 1997, Journal of immunology.

[20]  P. Lipsky,et al.  Bidirectional regulation of human B cell responses by CD40-CD40 ligand interactions. , 1997, Journal of immunology.

[21]  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.

[22]  R. Flavell,et al.  Expansion or Elimination of B Cells In Vivo: Dual Roles for CD40- and Fas (CD95)-Ligands Modulated by the B Cell Antigen Receptor , 1996, Cell.

[23]  R. Flavell,et al.  The Role of CD40 Ligand in Costimulation and T‐Cell Activation , 1996, Immunological reviews.

[24]  M. Crow,et al.  Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. , 1996, The Journal of clinical investigation.

[25]  M. Urashima,et al.  CD40 ligand triggers interleukin-6 mediated B cell differentiation. , 1996, Leukemia research.

[26]  P. Lipsky,et al.  Ligation of CD40 influences the function of human Ig-secreting B cell hybridomas both positively and negatively. , 1996, Journal of immunology.

[27]  R. Ramsey‐Goldman,et al.  Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. , 1996, The Journal of clinical investigation.

[28]  J. Norton,et al.  B cell early response gene expression coupled to B cell receptor, CD40 and interleukin‐4 receptor co‐stimulation: evidence for a role of the egr‐2/krox20 transcription factor in B cell proliferation , 1996, European journal of immunology.

[29]  F. Alt,et al.  CD40 expression and function in murine B cell ontogeny. , 1996, International immunology.

[30]  M. Cooper,et al.  Expression and function of Fas antigen on activated murine B cells , 1996, European journal of immunology.

[31]  H. Engelmann,et al.  A novel function of CD40: induction of cell death in transformed cells , 1996, The Journal of experimental medicine.

[32]  P. Krammer,et al.  CD40 ligation induces Apo-1/Fas expression on human B lymphocytes and facilitates apoptosis through the Apo-1/Fas pathway , 1995, The Journal of experimental medicine.

[33]  J. Karras,et al.  Induction of bcl-x by CD40 engagement rescues sIg-induced apoptosis in murine B cells. , 1995, Journal of immunology.

[34]  B Zheng,et al.  Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers. , 1995, Journal of immunology.

[35]  L. Davis,et al.  The CD40 ligand expressed by human B cells costimulates B cell responses. , 1995, Journal of immunology.

[36]  F. Alt,et al.  CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[37]  R J Armitage,et al.  Humoral immune responses in CD40 ligand-deficient mice , 1994, The Journal of experimental medicine.

[38]  T. Lebien,et al.  Cross-linking CD40 on human B cell precursors inhibits or enhances growth depending on the stage of development and the IL costimulus. , 1994, Journal of immunology.

[39]  H. Ochs,et al.  Costimulation through CD28 enhances T cell-dependent B cell activation via CD40-CD40L interaction. , 1994, Journal of immunology.

[40]  A. Aruffo,et al.  Signaling events during helper T cell-dependent B cell activation. I. Analysis of the signal transduction pathways triggered by activated helper T cell in resting B cells. , 1994, Journal of immunology.

[41]  G. Inghirami,et al.  T-BAM/CD40-L on helper T lymphocytes augments lymphokine-induced B cell Ig isotype switch recombination and rescues B cells from programmed cell death. , 1994, Journal of immunology.

[42]  R. Hardy,et al.  Deletion and editing of B cells that express antibodies to DNA. , 1994, Journal of immunology.

[43]  C. Hannum,et al.  Antibodies to murine CD40 stimulate normal B lymphocytes but inhibit proliferation of B lymphoma cells. , 1993, Cellular immunology.

[44]  I. Maclennan,et al.  Suppression of apoptosis in normal and neoplastic human B lymphocytes by CD40 ligand is independent of Bcl‐2 induction , 1993, European journal of immunology.

[45]  J. Banchereau,et al.  Human B cell precursors proliferate and express CD23 after CD40 ligation , 1993, The Journal of experimental medicine.

[46]  L. Herzenberg,et al.  Origin of murine B cell lineages. , 1993, Annual review of immunology.

[47]  E. Clark,et al.  Molecular and biological characterization of a murine ligand for CD40 , 1992, Nature.

[48]  I. Maclennan,et al.  Germinal center cells express bcl‐2 protein after activation by signals which prevent their entry into apoptosis , 1991, European journal of immunology.

[49]  J D Kemp,et al.  Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow , 1991, The Journal of experimental medicine.

[50]  C. Goodnow,et al.  The need for central and peripheral tolerance in the B cell repertoire. , 1990, Science.

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

[52]  S. Smith‐Gill,et al.  Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice , 1988, Nature.

[53]  P. Pereira,et al.  T Cell‐Dependent B Cell Activation , 1984, Immunological reviews.