Activation and immunoregulation of human B lymphocytes.

Immunocompetent cells communicate via direct cellular contact and/or by the release and binding of soluble mediators. These soluble mediators transmit signals for growth and differentiation of various cell types. We have been intensively studying the regulation of human B lymphocytes and have focused on the events which occur following stimulation of mature, resting B cells with antigen or an antigen equivalent, anti-immunoglobulin antibody. Anti-Ig stimulates resting B lymphocytes to enlarge, synthesize RNA, increase membrane Ia expression, express activation markers, and become responsive to soluble factors termed B-cell growth factors (BCGF). We have described two different BCGFs, an 18 kd BCGF derived from a T-T hybridoma and a 60 kd BCGF derived from a T cell line. Activated B cells in the presence of BCGF further enlarge; express another activation marker, the transferrin receptor; and enter the S phase of the cell cycle, but do not differentiate unless another factor is present, e.g., B-cell differentiation factor (BCDF). We have described another T-T hybridoma which constitutively secretes both an 18 kd BCGF and a 35 kd BCDF. These two factors can easily be separated by biochemical means. The 35 kd BCDF induces the differentiation of activated but not resting B cells. Besides these B-cell-specific factors, we have studied the immunoregulatory effects of interleukin 1 (IL-1), IL-2, and interferons (alpha and gamma) on human B-cell responses. Interleukin 1 weakly co-stimulates resting B cells when it is present with anti-Ig and enhances the differentiation of activated and proliferating B cells when it is present in culture with BCDF. Interleukin 2 receptors as defined by the monoclonal antibody anti-Tac and radiolabeled IL-2-binding assays are present on in vitro activated B cells. Recombinant IL-2 added to cultures of in vitro activated B cells promotes both B-cell growth and B-cell differentiation into Ig-secreting cells. Finally, interferons appear to have little direct effect on human B-cell function. Major advances in our understanding of the complexities of B-cell activation, proliferation, and differentiation have been realized over the past few years. The eventual isolation and chemical characterization of the soluble mediators of B-cell function and the receptors for these mediators should lead to further insights and to new approaches to those diseases characterized by aberrations of B-cell function.