The role of CD40L in T cell-dependent nitric oxide production by murine macrophages

Upon activation, T cells express CD40L, a member of the TNF cytokine superf amily, which serves as a ligand for CD40 on antigen presenting cells, inclu ding dendritic cells, B cells, and macrophages. While initial studies on th e function of CD40 focused its role in the regulation of B cell activation, more recent studies have indicated that CD40 ligation may be critical for the initiation of T cell-dependent macrophage activation, including stimula tion of nitric oxide production. However, the relative contribution of the CD40 pathway in macrophage nitric oxide production during T-dependent immun e responses remains unclear. We have found that while CD40 ligation of macr ophages can stimulate nitric oxide production, disruption of CD40 signaling during a T cell-mediated alloimmune response has no appreciable effect on nitric oxide production. If the T cell alloimmune response is restricted to CD4 cells, CD40L blockade has only a minimal effect on nitric oxide produc tion. Rather, IFN gamma, produced by alloactivated T cells, seems to be a n ecessary 'first' signal for nitric oxide production, while TNF alpha and CD 40L each provide independent 'second' signals. Finally, we demonstrate that CD40L stimulates macrophage NO production independent from autocrine TNF a lpha stimulation. These results suggest that macrophage nitric oxide produc tion during a T-dependent immune response requires IFN gamma production by CD4 cells whereas TNF alpha and CD40L can each provide important functional ly overlapping 'second' signals to costimulate nitric oxide production, tho ugh neither is required. (C) 2000 Elsevier Science B.V. All rights reserved .