ROLE OF THE CD40-CD40 LIGAND INTERACTION IN CD4(-CELL CONTACT-DEPENDENT ACTIVATION OF MONOCYTE INTERLEUKIN-1 SYNTHESIS() T)

Most studies of the induction of cytokine synthesis in monocytes have employed an exogenous triggering agent such as lipopolysaccharide. How ever, in nonseptic inflammatory responses (e.g. rheumatoid arthritis) monocyte activation occurs as a result of T cell-generated signals. In previous reports, we and others have demonstrated that contact-depend ent T cell-generated signals are capable of contributing to macrophage activation. We have shown that plasma membranes from anti-CD3 activat ed purified peripheral CD4(+) T cells (Tm-A) but not from resting CD4( +) cells (Tm-R) induce monocytes to synthesize interleukin (IL)-1 in t he absence of co-stimulatory cytokines. Studies to determine the expre ssion kinetics of the molecule(s) unique to activated CD4(+) T cells w hich interact with monocytes to induce IL-1 revealed that optimal expr ession occurred at 6 h post activation. This matched the previously re ported kinetics of expression of CD40 ligand (CD40L) on activated peri pheral T cells, implicating the CD40-CD40L interaction as a candidate for the initiator of the IL-1 signaling event. The ability of Tm-A to induce IL-1 synthesis in resting monocytes could be markedly reduced b y addition of a monoclonal anti-CD40L antibody, 5c8. In addition, a mo noclonal anti-CD40 IgM (BL-C4) proved dramatic in its ability to induc e resting monocytes to synthesize IL-1. In summary, these results demo nstrate that the CD40-CD40L interaction provides a critical component of CD4(+) T cell contact-dependent activation of monocyte IL-1 synthes is.