TUMOR-NECROSIS-FACTOR-ALPHA FACILITATES INDUCTION OF CD80 (B7-1) AND CD54 ON HUMAN B-CELLS BY ACTIVATED T-CELLS - COMPLEX REGULATION BY IL-4, IL-10, AND CD40L

Expression of immune accessory molecules, such as CD80 (B7-1), on antigen-presenting cells governs whether such cells can activate antigen-specific T cells. As such, the factors that regulate the expression of these accessory molecules may determine whether presentation of antigen leads to immune activation or anergy. We previously reported that anti-CD3-activated T cells (T-a) can induce expression of CD80 and CD54 (ICAM-1) on human B cells through a contact-dependent signal delivered to the CD40 molecule via the CD40 ligand. Here, we demonstrate that another molecule in the CD40-ligand family, namely tumor necrosis factor-alpha (TNF-alpha), also plays a role in the T-a-mediated induction of CD80 or CD54 on human B cells. Neutralizing mAbs specific for TNF-alpha can inhibit B cell expression of CD80 or CD54 that is induced when B cells are cultured with T-a cells or in T-a-cell conditioned media. Moreover, soluble, recombinant TNF-alpha or TNF-beta can induce significant increases in B cell expression of CD80 and CD54. The phenotypic changes effected by TNF-alpha can be recapitulated by crosslinking CD120b (p75 TNF-receptor), but not CD120a (p55 TNF-receptor), with mAbs presented on Fc gamma RII (CD32)-expressing L cells. IL-4 augments the expression of CD80 induced by crosslinking either CD40 or CD120b. However, although IL-10 augments CD40-induced expression of CD80, this cytokine inhibits the expression of CD80 that is induced by crosslinking CD120b. Further regulation of TNF- mediated CD80 expression may occur at the level of CD120b expression itself. We find that stimulation with exogenous IL-4 or CD40-crosslinking induces B cell expression of CD120b, but not CD120a. This study identifies an ancillary, TNF-mediated pathway, whereby activated T cells can induce B cells to express enhanced levels of the important co-stimulatory molecules, CD80 and CD54. (C) 1995 Academic Press, Inc.