title: Costimulation through CD28 enhances T cell-dependent B cell activation via CD40-CD40L interaction.
abstract: Changes in T cell helper function were analyzed when anti-CD3-activated T cells were costimulated with mAbs to the CD28 receptor (anti-CD28). T cell-dependent B cell growth and differentiation were consistently augmented if anti-CD3 stimulated-T cells were simultaneously activated with anti-CD28. Although anti-CD28 enhanced IL-2 and IL-4 production, it did not increase B cell responses solely by augmenting production of soluble lymphokines. Anti-CD28 costimulation induced increases on T cells of CD40 ligand (CD40L), known to promote B cell proliferation and Ig secretion. Because anti-CD28 promoted T cell helper functions and expression of CD40L, we examined the dependence for CD40L during T cell-dependent B cell responses. Although soluble CD40 fusion proteins only partially inhibited T cell-dependent B cell activation, we found a strict requirement for CD40L expression at initiating B cell responses. Both CD40L expression and T cell help were blocked by cyclosporin A after TCR cross-linking, and, unlike T cell proliferation, both remained cyclosporin A sensitive during CD28 costimulation. In addition, anti-CD28 could not compensate for the T cell helper deficiency of hyper IgM syndrome patients who lack functional CD40L. Thus, anti-CD28-induced T cell help is delivered via a CD40L-dependent process. The fact that cross-linking CD40 on B cells promotes expression of the B7/BB-1 ligand for CD28 suggest T and B interactions may have a reciprocal amplification mechanism.
authors.affiliation: Department of Microbiology, University of Washington, Seattle 98195.
authors.forename: S J
authors.initials: SJ
authors.lastname: Klaus
authors.forename: L M
authors.initials: LM
authors.lastname: Pinchuk
authors.forename: H D
authors.initials: HD
authors.lastname: Ochs
authors.forename: C L
authors.initials: CL
authors.lastname: Law
authors.forename: W C
authors.initials: WC
authors.lastname: Fanslow
authors.forename: R J
authors.initials: RJ
authors.lastname: Armitage
authors.forename: E A
authors.initials: EA
authors.lastname: Clark
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D018106:CD28 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens; D023201:CD40 Ligand; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D006942:Hypergammaglobulinemia / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood; D007136:Immunoglobulins / Q000096:biosynthesis; D066298:In Vitro Techniques; D008024:Ligands; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D018106:CD28 Antigens; D019013:CD40 Antigens; D007075:Immunoglobulin M; D007136:Immunoglobulins; D008024:Ligands; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D023201:CD40 Ligand; D016572:Cyclosporine