title: Role of CD40 in a T cell-mediated negative regulation of Ig production.
abstract: To investigate the possible role of CD40 in a negative regulation of Ig production, we used the mouse Ig allotype suppression model. T splenocytes from IGH(a/a) mice are able in vivo to totally and chronically inhibit the production of IgG(2a)(b) (IgG2a from the IGH(b) haplotype). Accordingly, postnatal transfer of IGH(a/a) T splenocytes into histocompatible IGH(a/b) F(1) or congenic IGH(b/b) mice leads to a characteristic IgG(2a)(b) suppression. The helper action of anti-IgG(2a)(b) CD4(+) T cells is required for the recruitment of anti-IgG(2a)(b) CD8(+) T suppression effectors. The latter use perforin (pore-forming protein, Pfp)- and/or Fas-dependent cytotoxic pathways to continuously eliminate B cells recently committed to IgG(2a)(b) production. In the present study we first showed that in vivo agonistic anti-CD40 mAb treatment of IGH(a/a) mice, deprived of their CD4(+) T cell compartment, could bypass the help of Ig allotype-specific CD4(+) T cells and generate CD8(+) T effector cells able to strongly inhibit IgG(2a)(b) production. This result demonstrates the usefulness of CD40 triggering in setting up an immune regulatory mechanism. Furthermore, with regard to the suppression-effector mechanism, we demonstrated that B cell CD40 expression was required for full suppression establishment via the Fas-dependent pathway. Indeed, IGH(a/a) PFP(degrees/degrees) T cells (using exclusively the Fas pathway) induced full IgG(2a)(b) suppression against IGH(b/b) CD40(+/+) B cells, but only partial inhibition of IgG(2a)(b) production against IGH(b/b) CD40(degrees/degrees) B cells. This finding provides the first demonstration of direct involvement of B cell CD40 expression in in vivo negative control of an Ig production.
authors.affiliation: Unité d'Immunophysiologie Moléculaire, Institut Pasteur, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Majlessi
authors.forename: G
authors.initials: G
authors.lastname: Bordenave
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology*; D006648:Histocompatibility / Q000235:genetics / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis; D007136:Immunoglobulins / Q000096:biosynthesis*; D007275:Injections, Intravenous; D008212:Lymphocyte Depletion; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007136:Immunoglobulins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D019014:fas Receptor