COSTIMULATION THROUGH CD28 ENHANCES T-CELL-DEPENDENT B-CELL ACTIVATION VIA CD40-CD40L INTERACTION

Changes in T cell helper function were analyzed when anti-CD3-activate d 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 activate d 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 a nd 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 respon ses. Both CD40L expression and T cell help were blocked by cyclosporin A after TCR cross-linking, and, unlike T cell proliferation, both rem ained cyclosporin A sensitive during CD28 costimulation. In addition, anti-CD28 could not compensate for the T cell helper deficiency of hyp er IgM syndrome patients who lack functional CD40L. Thus, anti-CD28-in duced 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 am plification mechanism.