Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help).

Abstract

SummaryCD4 + T lymphocytes provide contact-dependent stimuli to B cells that are critical for the generation of specific antibody responses in a process termed T helper function. The surface structures on activated CD4 + T cells that mediate this function are not fully known. We previously reported the isolation of a functionally unique subclone of the Jurkat leukemic T cell line (D1.1) that constitutively expressed contact-dependent helper effector function. To identify T cell surface molecules that mediate contact-dependent T helper function, a monoclonal antibody (mAb), designated 5c8, was generated that inhibits Dl.l-mediated B cell activation and immunoprecipitates a novel 30-kD protein structure from surface-iodinated D1.1 cells. Normal CD4 + T cells express 5c8 antigen (Ag) transiently after activation by phorbol myristate acetate and phytohemagglutinin with maximal expression 5-6 h after activation and absence of expression by 24 h. In contrast, neither resting nor activated CD8 § T cells express 5c8 Ag. In functional studies, mAb 5c8 inhibits the ability of fixed, activated CD4 § T cells to induce B cell surface CD23 expression. In addition, mAb 5c8 inhibits the ability of CD4 + T cells to direct terminal B cell differentiation driven by pokeweed mitogen. Taken together, these data suggest that 5c8 Ag is a novel, activation-induced surface T cell protein that is involved in mediating a contactdependent element of the helper effector function of CD4 § T lymphocytes.I n a contact-dependent process, termed T helper (Th) function, CD4 + T lymphocytes direct the activation and differentiation of B lymphocytes and thereby regulate the humoral immune response by modulating the specificity, secretion and isotype-encoded effector functions of antibody molecules (1-7). The T cell surface molecules that mediate the contact-dependent elements of Th cell function are not fully known.The process by which T cells help B cells to differentiate has been divided into two distinct phases: the inductive and the effector (8, 9). In the inductive phase, resting T cells contact antigen-primed B cells and this association allows clonotypic TCR-CD4 complexes to interact with Ia/Ag complexes on B cells (5, 10-16). TCP,/CD4 recognition of Ia/Ag results in the formation of stable T-B cognate pairs and bidirectional T and B cell activation (17-22). In the effector phase, activated T cells drive B cell differentiation by secreting lymphokines (23, 24) and by contact-dependent stimuli (20,(25)(26)(27)(28)(29)(30)(31)(32), both of which are required for T cells to drive small, resting B cells to terminally differentiate into Ig-secreting cells (25, 33, 34).Although the inductive phase of T cell help is Ag dependent and MHC restricted (5, 10-15, 34, 35), the effector phase of Th function can be Ag independent and MHC nonrestricted (25, 28, 30, 34,(36)(37)(38)(39)(40)(41)(42)(43)). An additional contrasting feature is that the inductive phase of T cell help often requires CD4 molecules and is inhibited by anti-CD4 mAb (16), whereas help...

The role of polar interactions in the molecular recognition of CD40L with its receptor CD40

“…We verified that all mutant CD4OLs were expressed and indirectly assessed their structural integrity by immunoprecipitation of detergent lysates from metabolically labeled cells with polyclonal antibodies directed against synthetic peptides corresponding to the N-and C-terminal portion of CD4OL (Hsu et al, 1997), or with the anti-CD4OL mAb 5c8 (Fig. 7), which can block CI)rU)/CD40L-mediated signaling (Lederman et al, 1992;Yellin et al, 1994). Cell surface expression of CD4OL of selected mutants positive for 5c8 binding was verified by FACS staining of intact assayed by binding to the N-and C-terminal-specific antisera (Table 1).…”

Th2-Dependent B Cell Responses in the Absence of CD40-CD40 Ligand Interactions

“…Other more complex steps in B cell development, such as germinal center formation, somatic hypermutation, and creation of memory, clearly require CD40L-CD40, as demonstrated by murine models in which these pathways are inhibited by germline mutations, infusion of blocking Abs, or soluble receptors (12)(13)(14)(15)(16)(17). A few reports have demonstrated CD40-independent B cell responses in T cell-independent systems (9,39,40). However, the in vivo role of T celldependent responses in the absence of CD40L-CD40 interactions have not been studied.…”

Critical role of lipid rafts in CD154‐mediated T cell signaling

“…T lymphocytes Introduction CD154 is a type II transmembrane protein, member of the TNF superfamily, originally detected on the surface of stimulated CD4 1 T cells. Since then, CD154 was found on the surface of activated CD8 1 T cells, gd T cells, B cells, basophils, mast cells, macrophages, dendritic cells, activated platelets, and nonhematopoietic cells such as endothelial cells and fibroblasts [1][2][3][4][5][6][7]. In addition to its transmembrane form, CD154 is also released as a soluble protein by cleavage of the extracellular domain [8,9].…”