RAPID INDUCTION OF A NOVEL COSTIMULATORY ACTIVITY ON B-CELLS BY CD40 LIGAND

Background: T cells and B cells communicate by direct cell-cell interaction that is crucial to the functioning of the immune system. It is well, established that the interaction between B-cell-expressed CD40 and T-cell-expressed CD40 ligand (CD40L) is critical for T-cell-dependent antibody responses, but the role of this interaction in T-cell responses is less clear. In this study, we have used mice with targeted mutations in the genes encoding CD40L or CD28 to investigate how the CD40-CD40L interaction induces on B cells a costimulatory activity that acts in addition to antigen to trigger T-cell growth. Results: We show that T cells from CD40L-deficient mice induce a substantially reduced costimulatory activity on B cells compared to wild-type T cells, particularly at early time points. Surprisingly, T cells from CD40L-deficient mice induce similar levels of B7-1 and B7-2 as do wild-type T cells. We further show that the CD40L-mediated induction of costimulatory activity precedes the induction of B7-1, B7-2 and the heat-stable antigen (HSA). CD4 T cells isolated from the CD28-deficient mice can receive costimulatory activity from CD40L-induced B cells, demonstrating that the induced molecules can costimulate T cells by a CD28-independent mechanism. We have generated a novel monoclonal antibody that inhibits the CD40L-induced costimulatory activity. Expression of the epitope detected by this monoclonal antibody correlates with the induction oi the costimulatory activity, and the molecule recognized by the monoclonal antibody is a single chain of around 85 kDa, distinct from B7-1, B7-2, ICAM-1, ICAM-2, ICAM-3, HSA, CD5, integrin and 4-1BB ligand. Conclusions: Our results demonstrate that CD40L is both necessary and sufficient for rapid, T-cell-mediated induction of costimulatory activity on B cells. This costimulatory activity is distinct from B7-1 and B7-2, and is independent of CD28.