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CD40L interaction — all things to all immunologists
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Res. Immunol. 1994, 145, 199-249
INSTITUT PASTEUR/ELSEVIER
Paris 1994
57th FORUM IN IMMUNOLOGY
THE CD40/CD40L INTERACTION ALL THINGS TO ALL IMMUNOLOGISTS Organized by J.Y. Bonnefoy and R.J. Noelle
Introduction Collaboration between activated T cells and B cells is mediated by both soluble cytokines and contact-dependent cell-surface interactions. Those two sets of signals determine B-cell responses such as isotype switching and antibody production. Among various cell surface molecules implicated, interaction between CD40 on antigen-presenting cells, including B cells, and CD40L on activated T cells have recently been shown to be of major importance. The importance of CD40, especially in B-cell responses, has led many groups to search for its ligand. The proposed importance of the CD40/ CD40L interaction exceeded expectations after it was shown by several groups that a direct link existed between CD4OL defects and the human immunodeficiency, X-linked hyper-IgMl syndrome (HIGMl). CD40 is a type I integral membrane glycoprotein which belongs to the family of TNF/NGF receptors. CD40 is expressed on B cells, interdigitating cells, different types of dendritic cells, thymic epithelial cells, monocytes, T cells and some carcinomas. The physiological function of CD40 expression on T cells is not very clear, as discussed by Aversa et al. CD40L (gp39, T-BAM or TRAP) is a type II integral membrane glycoprotein with a predicted tertiary structure similar to the TNF family. It possesses one potential cleavage site. Both membrane-bound and soluble CD40L (probably as a trimeric form) exhibit biological activities. CD40L is expressed on T cells and also on eosinophils, basophils and mast cells (Gauchat et al.).
The CD4O/CD4OL interaction plays a central role in vivo both under normal and disease conditions. In normal situations, the CD40/CD40L interaction plays a role in thymic education as well as tolerance of mature peripheral T cells, possibly by regulation of costimulatory molecule expression, as discussed by Durie et al. CD40-CD40L pairing also plays a key role in the T cell/B cell interaction by regulating immunoglobulin switching (Lederman et al.; Di Santo et al.) including IgE (Gauchat et al.; Aversa et al.). CD40L may have some role in germinal centre formation, since germinal centres are absent in HIGM 1 patients, as discussed by Lederman et al. CD40 engagement is not only important in the induction of Ig isotype switching (Aversa et al.; Caux et al. ; Gauchat et al.), but it also participates in the initiation of T-cell-dependent responses of both naive and memory B cells (Splawski et al.). Nevertheless, CD40L induces B-cell differentiation only when B cells have passed the pre-B-celI stage (Aversa et al.). On dendritic cells, CD40 triggering induce morphological and phenotypical changes, including expression of accessory molecules which may contribute to enhancing antigen-presenting capacity as well as the secretion of cytokines and chemokines (Caux et al.). In humans, the finding that CD4OL defects cause HIGMl demonstrated the importance of this molecule in isotype switching (discussed by Di Santo et al. ; Ochs et al. ; Splawski et al.). A possible further consequence of mutated CD40L that contributes to immunodeficiency could be an impaired bacteri-
57th FORUM
200
tidal function of monocytes, since it has recently been shown that ligation of CD40 on monocytes with CD40L potentiates both cytokine production and tumoricidal activity. These findings again highlight how the study of a human disease can contribute to the understanding of physiology. B cells from HIGMl patients can be induced to switch to all Ig isotypes by engagement of CD40 (Di Santo et al. ; Splawski et al.), confirming that the defect in the HIGMl syndrome is on the T-cell rather than on the B-cell side. In animal models, the CD40-CD40L interaction has been shown to play a major role in antibody- and T-cell-mediated autoimmune diseases, including rheumatoid arthritis and experimental allergic encephalomyelitis in mice, probably by affecting macrophage functions (Durie et al.). In line with these findings, CD40L on T cells from patients suffering from rheumatoid arthritis and psoriasis show increased CD40L expression (Lederman et al.). Mast cells and basophils can express CD40L, which is shown to be able to provide, in conjunction
IN IMMUNOLOGY with IL4, the minimal signals required to induce IgE production (Gauchat et al.). This suggests that mast cells and basophils are likely to play an important role in the induction and maintenance of allergic reactions. Thus, Ig switching previously thought to take place only in lymph node germinal centres may also occur in peripheral organs such as the lung or the skin. Altogether, CD4OCD4OL pairing, as discussed in this Forum, plays a critical role in important aspects of immune regulation, and dysregulation of this interaction can lead to severe diseases. J.-Y. Bonnefoy
Glaxo Institute for Molecular Biology, 1228 Plan-les-Ouates, Geneva (Switzerland) and R.J. Noelle
Dartmouth Medical School, Department of Microbiology, 640 W. Borwell Building, Lebanon, NH 03756 (USA)
The role of CD40 and its ligand (gp39) in peripheral and central tolerance and its contribution to autoimmune disease F.H. Durie, T.M. Foy and R. J. Noelle (*I Department
of Microbiology,
Dartmouth Medical School, One Medical Lebanon, NH, 03756 (USA)
The role of gp39-CD40 interactions in humoral immunity has been well established in both mice and humans. Recent studies implicate this ligand-receptor pair in thymic education, as well as tolerance of mature peripheral T cells. The role of gp39 in the development of helper T-cell(T,)-dependent B-cell responses, as well as cell-mediated immune responses, has led researchers to investigate the nature of this interaction in the development of both antibody- and T-cell-mediated autoimmune diseases.
(*) To whom correspondence should be sent.
The role of gp39 in thymic
Center Drive,
education
Negative selection is a process by which immature T cells encounter their antigen during development and are clonally deleted. Negative selection has been demonstrated in a number of independent systems (reviewed by Marrack et al., 1993). The first demonstration of negative selection was reported utilizing a monoclonal anti-T-cell receptor (TCR) VP antibody. Thymocytes expressing VP17 were elimi-
Res. Immunol. 1994, 145, 199-249
INSTITUT PASTEUR/ELSEVIER
Paris 1994
57th FORUM IN IMMUNOLOGY
THE CD40/CD40L INTERACTION ALL THINGS TO ALL IMMUNOLOGISTS Organized by J.Y. Bonnefoy and R.J. Noelle
Introduction Collaboration between activated T cells and B cells is mediated by both soluble cytokines and contact-dependent cell-surface interactions. Those two sets of signals determine B-cell responses such as isotype switching and antibody production. Among various cell surface molecules implicated, interaction between CD40 on antigen-presenting cells, including B cells, and CD40L on activated T cells have recently been shown to be of major importance. The importance of CD40, especially in B-cell responses, has led many groups to search for its ligand. The proposed importance of the CD40/ CD40L interaction exceeded expectations after it was shown by several groups that a direct link existed between CD4OL defects and the human immunodeficiency, X-linked hyper-IgMl syndrome (HIGMl). CD40 is a type I integral membrane glycoprotein which belongs to the family of TNF/NGF receptors. CD40 is expressed on B cells, interdigitating cells, different types of dendritic cells, thymic epithelial cells, monocytes, T cells and some carcinomas. The physiological function of CD40 expression on T cells is not very clear, as discussed by Aversa et al. CD40L (gp39, T-BAM or TRAP) is a type II integral membrane glycoprotein with a predicted tertiary structure similar to the TNF family. It possesses one potential cleavage site. Both membrane-bound and soluble CD40L (probably as a trimeric form) exhibit biological activities. CD40L is expressed on T cells and also on eosinophils, basophils and mast cells (Gauchat et al.).
The CD4O/CD4OL interaction plays a central role in vivo both under normal and disease conditions. In normal situations, the CD40/CD40L interaction plays a role in thymic education as well as tolerance of mature peripheral T cells, possibly by regulation of costimulatory molecule expression, as discussed by Durie et al. CD40-CD40L pairing also plays a key role in the T cell/B cell interaction by regulating immunoglobulin switching (Lederman et al.; Di Santo et al.) including IgE (Gauchat et al.; Aversa et al.). CD40L may have some role in germinal centre formation, since germinal centres are absent in HIGM 1 patients, as discussed by Lederman et al. CD40 engagement is not only important in the induction of Ig isotype switching (Aversa et al.; Caux et al. ; Gauchat et al.), but it also participates in the initiation of T-cell-dependent responses of both naive and memory B cells (Splawski et al.). Nevertheless, CD40L induces B-cell differentiation only when B cells have passed the pre-B-celI stage (Aversa et al.). On dendritic cells, CD40 triggering induce morphological and phenotypical changes, including expression of accessory molecules which may contribute to enhancing antigen-presenting capacity as well as the secretion of cytokines and chemokines (Caux et al.). In humans, the finding that CD4OL defects cause HIGMl demonstrated the importance of this molecule in isotype switching (discussed by Di Santo et al. ; Ochs et al. ; Splawski et al.). A possible further consequence of mutated CD40L that contributes to immunodeficiency could be an impaired bacteri-
57th FORUM
200
tidal function of monocytes, since it has recently been shown that ligation of CD40 on monocytes with CD40L potentiates both cytokine production and tumoricidal activity. These findings again highlight how the study of a human disease can contribute to the understanding of physiology. B cells from HIGMl patients can be induced to switch to all Ig isotypes by engagement of CD40 (Di Santo et al. ; Splawski et al.), confirming that the defect in the HIGMl syndrome is on the T-cell rather than on the B-cell side. In animal models, the CD40-CD40L interaction has been shown to play a major role in antibody- and T-cell-mediated autoimmune diseases, including rheumatoid arthritis and experimental allergic encephalomyelitis in mice, probably by affecting macrophage functions (Durie et al.). In line with these findings, CD40L on T cells from patients suffering from rheumatoid arthritis and psoriasis show increased CD40L expression (Lederman et al.). Mast cells and basophils can express CD40L, which is shown to be able to provide, in conjunction
IN IMMUNOLOGY with IL4, the minimal signals required to induce IgE production (Gauchat et al.). This suggests that mast cells and basophils are likely to play an important role in the induction and maintenance of allergic reactions. Thus, Ig switching previously thought to take place only in lymph node germinal centres may also occur in peripheral organs such as the lung or the skin. Altogether, CD4OCD4OL pairing, as discussed in this Forum, plays a critical role in important aspects of immune regulation, and dysregulation of this interaction can lead to severe diseases. J.-Y. Bonnefoy
Glaxo Institute for Molecular Biology, 1228 Plan-les-Ouates, Geneva (Switzerland) and R.J. Noelle
Dartmouth Medical School, Department of Microbiology, 640 W. Borwell Building, Lebanon, NH 03756 (USA)
The role of CD40 and its ligand (gp39) in peripheral and central tolerance and its contribution to autoimmune disease F.H. Durie, T.M. Foy and R. J. Noelle (*I Department
of Microbiology,
Dartmouth Medical School, One Medical Lebanon, NH, 03756 (USA)
The role of gp39-CD40 interactions in humoral immunity has been well established in both mice and humans. Recent studies implicate this ligand-receptor pair in thymic education, as well as tolerance of mature peripheral T cells. The role of gp39 in the development of helper T-cell(T,)-dependent B-cell responses, as well as cell-mediated immune responses, has led researchers to investigate the nature of this interaction in the development of both antibody- and T-cell-mediated autoimmune diseases.
(*) To whom correspondence should be sent.
The role of gp39 in thymic
Center Drive,
education
Negative selection is a process by which immature T cells encounter their antigen during development and are clonally deleted. Negative selection has been demonstrated in a number of independent systems (reviewed by Marrack et al., 1993). The first demonstration of negative selection was reported utilizing a monoclonal anti-T-cell receptor (TCR) VP antibody. Thymocytes expressing VP17 were elimi-