title: CD4 binding to major histocompatibility complex class II antigens induces LFA-1-dependent and -independent homotypic adhesion of B lymphocytes.
abstract: T helper cells recognize processed antigen (Ag) in the context of major histocompatibility complex (MHC) class II antigens present on the surface of B cells and other Ag-presenting cells. This interaction is mediated through the T cell receptor complex with associate recognition of class II molecules by the CD4 molecule. In this study, the binding of a soluble recombinant CD4/Ig heavy chain fusion protein (CD4-gamma 3) or monoclonal antibody (mAb) to class II antigens on human B cells was shown to induce rapid and specific homotypic adhesion of B cells and most B lymphoblastoid cell lines. mAb reactive with CD4 inhibited CD4-gamma 3-induced adhesion and a mutant B lymphoblastoid cell line deficient in class II antigens failed to respond. Induction of homotypic adhesion was dependent on energy metabolism and a functional cytoskeleton, and class II+ pre-B cells did not exhibit adhesion in response to these stimuli, suggesting that cross-linking of class II molecules generated a transmembrane signal and did not simply aggregate cells. In addition, MHC class II-induced adhesion was Fc receptor independent, as 15 mAb of different Ig isotypes reactive with HLA-D or HLA-DQ gene products induced adhesion. Anti-class II mAb and CD4-gamma 3 were able to induce adhesion at concentrations as low as 10 ng/ml and 100 ng/ml, respectively. Suboptimal stimulation of B cell lines through HLA-D antigens induced homotypic adhesion that was dependent on the activation of LFA-1 (CD11a/CD18), and which could be blocked by specific mAb. However, at greater signal strengths, adhesion was not blocked by mAb against the known adhesion receptors, suggesting the induction of a novel adhesion pathway. Consistent with this, homotypic adhesion induced by engagement of MHC class II antigens was observed with LFA-1-deficient B cell lines, and was independent of CD49d or CD18 expression. Thus, the direct engagement of B cell class II antigens by CD4 is likely to generate transmembrane signals which trigger both LFA-1-dependent and LFA-1-independent adhesion pathways.
authors.affiliation: Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA 02115-6084.
authors.forename: G S
authors.initials: GS
authors.lastname: Kansas
authors.forename: J C
authors.initials: JC
authors.lastname: Cambier
authors.forename: T F
authors.initials: TF
authors.lastname: Tedder
mesh_terms: D001402:B-Lymphocytes / Q000502:physiology*; D015704:CD4 Antigens / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D006681:HLA-D Antigens / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D015704:CD4 Antigens; D006681:HLA-D Antigens; D000949:Histocompatibility Antigens Class II; D016169:Lymphocyte Function-Associated Antigen-1; D011994:Recombinant Proteins; D013755:Tetradecanoylphorbol Acetate