Immune regulation by CD40 and its ligand GP39.

Over the past three years, CD40 and its ligand (gp39, CD40L, TBAM) have been shown to be essential for humoral immune responses to thymus-dependent antigens. However, as the tissue distribution widens for those cells that express CD40 and gp39, we can now show that this ligand-receptor pair also plays an important role in the selection of self-reactive T cells in the thymus (central tolerance) and the regulation of tolerance in mature T cells (peripheral tolerance). Advances in our understanding of the molecular basis for CD40 biology is based in two areas of research. First, a major breakthrough in our understanding of how CD40 transduces biological events centers on the identification of a novel protein that binds to the cytoplasmic tail of CD40 and may act as a signal transducing molecule. Secondly, advances in molecular modeling and mutagenesis of this ligand-receptor pair have helped to identify the critical receptor/ligand contacts in the gp39/CD40 complex. Advances in each of these areas are discussed.

[1]  B. Fowlkes,et al.  Selective events in T cell development. , 1994, Annual review of immunology.

[2]  R. Geha,et al.  Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase C gamma 2 , 1994, The Journal of experimental medicine.

[3]  T. Rothstein,et al.  Receptor-specific induction of individual AP-1 components in B lymphocytes. , 1995, Journal of immunology.

[4]  S. Hedrick,et al.  In vivo and in vitro clonal deletion of double-positive thymocytes , 1992, The Journal of experimental medicine.

[5]  A. Fischer,et al.  T cell clones from an X-linked hyper-immunoglobulin (IgM) patient induce IgE synthesis in vitro despite expression of nonfunctional CD40 ligand , 1994, The Journal of experimental medicine.

[6]  T. Kipps,et al.  Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal , 1993, The Journal of experimental medicine.

[7]  J. Banchereau,et al.  The CD40 antigen and its ligand. , 1994, Annual review of immunology.

[8]  S. Sprang,et al.  The structure of tumor necrosis factor-alpha at 2.6 A resolution. Implications for receptor binding. , 1990, The Journal of biological chemistry.

[9]  R. Flavell,et al.  Mice deficient for the CD40 ligand. , 1994, Immunity.

[10]  Jing Wu,et al.  B-cell apoptosis induced by antigen receptor crosslinking is blocked by a T-cell signal through CD40 , 1993, Nature.

[11]  P. Marrack,et al.  Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells. , 1990, Science.

[12]  R. Flavell,et al.  An essential role for gp39, the ligand for CD40, in thymic selection , 1995, The Journal of experimental medicine.

[13]  L. Lanier,et al.  B70 antigen is a second ligand for CTLA-4 and CD28 , 1993, Nature.

[14]  N. Yoshida,et al.  The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. , 1994, Immunity.

[15]  J. Ceuppens,et al.  Ligation of B7 with CD28/CTLA‐4 on T cells results in CD40 ligand expression, interleukin‐4 secretion and efficient help for antibody production by B cells , 1993, European journal of immunology.

[16]  P. Linsley,et al.  T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[17]  B. Hausmann,et al.  Mice transgenic for a soluble form of murine CTLA-4 show enhanced expansion of antigen-specific CD4+ T cells and defective antibody production in vivo , 1994, The Journal of experimental medicine.

[18]  R. Noelle,et al.  Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[19]  I. Maclennan,et al.  Germinal centres in T-cell-dependent antibody responses. , 1992, Immunology today.

[20]  J. Allison,et al.  Identification and distribution of the costimulatory receptor CD28 in the mouse. , 1992, Journal of immunology.

[21]  P. Linsley,et al.  Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. , 1992, Science.

[22]  P. Linsley,et al.  Tolerance induction by soluble CTLA4 in a mouse skin transplant model. , 1994, Transplantation proceedings.

[23]  A. Aruffo,et al.  gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory , 1994, The Journal of experimental medicine.

[24]  P. Linsley,et al.  Studies on the interdependence of gp39 and B7 expression and function during antigen‐specific immune responses , 1995, European journal of immunology.

[25]  M C Peitsch,et al.  A 3-D model for the CD40 ligand predicts that it is a compact trimer similar to the tumor necrosis factors. , 1993, International immunology.

[26]  J. Parsons,et al.  CD40 signaling pathway: anti-CD40 monoclonal antibody induces rapid dephosphorylation and phosphorylation of tyrosine-phosphorylated proteins including protein tyrosine kinase Lyn, Fyn, and Syk and the appearance of a 28-kD tyrosine phosphorylated protein , 1994, The Journal of experimental medicine.

[27]  W. Fanslow,et al.  CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40 , 1993, The Journal of experimental medicine.

[28]  A. Aruffo,et al.  Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-vs-host disease. , 1994, The Journal of clinical investigation.

[29]  P. Linsley,et al.  B7 costimulates proliferation of CD4-8+ T lymphocytes but is not required for the deletion of immature CD4+8+ thymocytes. , 1992, Journal of immunology.

[30]  P. J. Belshaw,et al.  Cyclosporin A inhibits CD40 ligand expression in T lymphocytes. , 1994, The Journal of clinical investigation.

[31]  A. Aruffo,et al.  In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39 , 1993, The Journal of experimental medicine.

[32]  J. Hansen,et al.  Suppressed antidonor MLC responses in renal transplant candidates conditioned with donor-specific transfusions that carry the recipient's noninherited maternal HLA haplotype. , 1990, Transplantation.

[33]  P. Linsley,et al.  Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion , 1993, The Journal of experimental medicine.

[34]  L. Hood,et al.  Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity , 1993, Cell.

[35]  J. Belmont,et al.  CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome , 1993, Science.

[36]  J. Bluestone,et al.  The B7 and CD28 receptor families. , 1994, Immunology today.

[37]  T. Chiles,et al.  T cell-dependent induction of NF-kappa B in B cells , 1993, The Journal of experimental medicine.

[38]  H. Nariuchi,et al.  Mechanisms of T cell contact-dependent B cell activation. , 1994, Journal of immunology.

[39]  D. Parker,et al.  Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. , 1992 .

[40]  G. Schieven,et al.  Stimulation of protein tyrosine phosphorylation, phosphoinositide turnover, and multiple previously unidentified serine/threonine-specific protein kinases by the Pan-B-cell receptor CD40/Bp50 at discrete developmental stages of human B-cell ontogeny. , 1991, The Journal of biological chemistry.

[41]  P. Lipsky,et al.  The role of CD40-CD40 ligand interaction in human T cell-B cell collaboration. , 1994, Journal of immunology.

[42]  A. Kruisbeek,et al.  The role of LFA-1/ICAM-1 interactions during murine T lymphocyte development. , 1991, Journal of immunology.

[43]  P. Linsley,et al.  Induction and reversal of long-lived specific unresponsiveness to a T-dependent antigen following CTLA4Ig treatment. , 1995, Journal of immunology.

[44]  G. Gray,et al.  Coblockade of the LFA1:ICAM and CD28/CTLA4:B7 pathways is a highly effective means of preventing acute lethal graft-versus-host disease induced by fully major histocompatibility complex-disparate donor grafts. , 1995, Blood.

[45]  P. Linsley,et al.  Transplantation tolerance induced by CTLA4-Ig. , 1994, Transplantation.

[46]  J Bajorath,et al.  Identification of residues on CD40 and its ligand which are critical for the receptor-ligand interaction. , 1995, Biochemistry.

[47]  J. Bajorath,et al.  The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome , 1993, Cell.

[48]  C. Maliszewski,et al.  The regulation of T cell-dependent antibody formation in vitro by CD40 ligand and IL-2. , 1993, Journal of immunology.

[49]  L. Tartaglia,et al.  Two TNF receptors. , 1992, Immunology today.

[50]  J. Sprent,et al.  B7 expression on thymic medullary epithelium correlates with epithelium-mediated deletion of V beta 5+ thymocytes. , 1994, Journal of immunology.

[51]  P. Linsley,et al.  The effect of combination cyclosporine and CTLA4-Ig therapy on cardiac allograft survival. , 1994, The Journal of surgical research.

[52]  F. Fitch,et al.  IL-4-producing CD8+ T cell clones can provide B cell help. , 1995, Journal of immunology.

[53]  I. Stamenkovic,et al.  Identification of the intracytoplasmic region essential for signal transduction through a B cell activation molecule, CD40 , 1990, European journal of immunology.

[54]  J. Banchereau,et al.  Activation of human dendritic cells through CD40 cross-linking , 1994, The Journal of experimental medicine.

[55]  R. Geha,et al.  gamma/delta T lymphocytes express CD40 ligand and induce isotype switching in B lymphocytes , 1995, The Journal of experimental medicine.

[56]  A. Singer,et al.  Negative selection of CD4+CD8+ thymocytes by T cell receptor-induced apoptosis requires a costimulatory signal that can be provided by CD28 , 1994, The Journal of experimental medicine.

[57]  H. Ochs,et al.  The Role of CD40 and its Ligand in the Regulation of the Immune Response , 1994, Immunological Reviews.

[58]  J. Pober,et al.  CD40 on human endothelial cells: inducibility by cytokines and functional regulation of adhesion molecule expression. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[59]  H. Spits,et al.  CD40 is functionally expressed on human thymic epithelial cells. , 1992, Journal of immunology.

[60]  R. Coffman,et al.  Membranes from both Th1 and Th2 T cell clones stimulate B cell proliferation and prepare B cells for lymphokine-induced differentiation to secrete Ig. , 1991, Journal of immunology.

[61]  M. Cooke,et al.  Differential up-regulation of the B7-1 and B7-2 costimulatory molecules after Ig receptor engagement by antigen. , 1994, Journal of immunology.

[62]  G. Gray,et al.  The role of T cell subsets in regulating the in vivo efficacy of CTLA4-Ig in preventing graft-versus-host disease in recipients of fully MHC or multiple minor histocompatibility-disparate donor inocula. , 1994, Transplantation.

[63]  R. Noelle,et al.  Contact-dependent B-cell activation by helper T cells. , 1990, Research in immunology.

[64]  J. Bonnefoy,et al.  CD40 ligand is functionally expressed on human eosinophils , 1995, European journal of immunology.

[65]  R. Steinman,et al.  The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro , 1994, The Journal of experimental medicine.

[66]  P. Marrack,et al.  T cell tolerance by clonal elimination in the thymus , 1987, Cell.

[67]  R. Flavell,et al.  In the absence of a CD40 signal, B cells are tolerogenic. , 1995, Immunity.

[68]  S. Lederman,et al.  Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help) , 1992, The Journal of experimental medicine.

[69]  D. I. Stuart,et al.  Structure of tumour necrosis factor , 1989, Nature.

[70]  H. Teh,et al.  Deletion of antigen-specific immature thymocytes by dendritic cells requires LFA-1/ICAM interactions. , 1992, Journal of immunology.

[71]  A. Fischer,et al.  CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM , 1993, Nature.

[72]  D. Campana,et al.  Hyper IgM syndrome associated with defective CD40-mediated B cell activation. , 1994, The Journal of clinical investigation.

[73]  A. Aruffo,et al.  The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. , 1993, Journal of immunology.

[74]  K. Kishi,et al.  Induction of human IgE synthesis in B cells by mast cells and basophils , 1993, Nature.

[75]  C. Ware,et al.  The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family , 1995, Cell.

[76]  E. Clark,et al.  CD40: a cytokine receptor in search of a ligand. , 1990, Tissue antigens.

[77]  D. Goeddel,et al.  A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor , 1994, Cell.

[78]  P. Linsley,et al.  Signal transduction via CD4, CD8, and CD28 in mature and immature thymocytes. Implications for thymic selection. , 1991, Journal of immunology.

[79]  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.

[80]  P. Linsley,et al.  In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. , 1994, Blood.

[81]  R. Schwartz,et al.  Effects of cyclosporine A on T cell development and clonal deletion. , 1988, Science.

[82]  L. Lanier,et al.  CD40 preferentially costimulates activation of CD4+ T lymphocytes. , 1994, Journal of immunology.

[83]  John Calvin Reed,et al.  A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40 , 1995, FEBS letters.

[84]  D. Gray,et al.  Activated human T cells express a ligand for the human B cell‐associated antigen CD40 which participates in T cell‐dependent activation of B lymphocytes , 1992, European journal of immunology.

[85]  P. Bretscher.  The two-signal model of lymphocyte activation twenty-one years later. , 1992, Immunology today.

[86]  M. Boguski,et al.  A novel RING finger protein interacts with the cytoplasmic domain of CD40. , 1994, The Journal of biological chemistry.

[87]  C. Janeway,et al.  Induction of B cell costimulatory function by recombinant murine CD40 ligand , 1994, European journal of immunology.

[88]  P. Kiener,et al.  Expression of functional CD40 by vascular endothelial cells , 1995, The Journal of experimental medicine.

[89]  P. Linsley,et al.  Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. , 1992, Science.

[90]  D. Baltimore,et al.  Involvement of CRAF1, a relative of TRAF, in CD40 signaling , 1995, Science.

[91]  I. Maclennan,et al.  A subset of CD4+ memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T cell receptor complex , 1995, The Journal of experimental medicine.

[92]  S. Jameson,et al.  Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor , 1989, Nature.

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

[94]  P. Matzinger,et al.  B cells turn off virgin but not memory T cells. , 1992, Science.

[95]  R. Schwartz,et al.  Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[96]  A. Aruffo,et al.  In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines, and antibody production delineates sites of cognate T-B cell interactions , 1993, The Journal of experimental medicine.

[97]  G. Inghirami,et al.  Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help. , 1992, Journal of immunology.

[98]  J Bajorath,et al.  Analysis of gp39/CD40 interactions using molecular models and site-directed mutagenesis. , 1995, Biochemistry.

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

[100]  P. Linsley,et al.  Comparative analysis of B7-1 and B7-2 costimulatory ligands: expression and function , 1994, The Journal of experimental medicine.

[101]  D. Gray,et al.  Memory B cell development but not germinal center formation is impaired by in vivo blockade of CD40-CD40 ligand interaction , 1994, The Journal of experimental medicine.

[102]  L. Notarangelo,et al.  Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM , 1993, Nature.

[103]  J. Allison,et al.  Two signals are required for negative selection of CD4+CD8+ thymocytes. , 1993, Journal of immunology.

[104]  S R Sprang,et al.  The structure of human lymphotoxin (tumor necrosis factor-beta) at 1.9-A resolution. , 1992, The Journal of biological chemistry.

[105]  J. Tavernier,et al.  Structure-activity studies of human tumour necrosis factors. , 1994, Protein engineering.

[106]  D. Banner,et al.  Crystal structure of the soluble human 55 kd TNF receptor-human TNFβ complex: Implications for TNF receptor activation , 1993, Cell.

[107]  J. Gordon,et al.  Protein tyrosine phosphorylation is mandatory for CD40‐mediated rescue of germinal center B cells from apoptosis , 1993, European journal of immunology.

[108]  J. Banchereau,et al.  Generation of memory B cells and plasma cells in vitro , 1995, Science.