[Frontiers in Bioscience 2, d197-206, May 1, 1997]
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T CELL SIGNALING OF MACROPHAGE FUNCTION IN INFLAMMATORY DISEASE

Robert D. Stout1 and Jill Suttles2

Program in Immunology, Departments of Microbiology1 and Biochemistry2, James H. Quillen College of Medicine at East Tennessee State University, Johnson City, TN, USA

Received 4/15/97; Accepted 4/18/97; On-line 5/1/97

5. CONTACT-DEPENDENT SIGNALING OF MACROPHAGE ACTIVATION.

CD40:CD40L is the receptor:ligand pair that has received the most attention in the context of contact-dependent signaling of B cells and macrophages (34,84-87). CD40L is expressed transiently upon activation of T cells, with maximum expression usually observed at 5-10 hrs (88,89). Anti-CD40L antibody interferes with T cell signaling of macrophage accessory function, cytokine production and nitric oxide generation (24,25,28). Conversely, anti-CD40 antibody (28), CD40L-transfected cells (29), or soluble trimeric CD40L (27) induce expression of accessory molecules and production of a full array of cytokines (IL-1, TNF-alpha, IL-6, IL-10, IL-12) by macrophages. However, although anti-CD40L antibody nearly completely blocks induction of IL-1 release and CD80 expression by isolated T cell membranes or fixed T cells (25,28), it only partially blocks nitric oxide generation and CD86 expression (24,25). These observations suggested that CD40 ligation is not solely responsible for T cell contact-dependent signaling. This was confirmed by the observation that T cells from CD40L-deficient mice can activate macrophage nitric oxide generation via contact-dependent signaling (31). Although CD40L-deficient T cells, paraformaldehyde-fixed after being activated for 5 hrs on anti-CD3, lacked the ability to signal macrophage nitric oxide production, CD40L-deficient T cells, fixed after being activated for 24 hrs on anti-CD3, were able to signal macrophage nitric oxide production as effectively as similarly activated normal T cells (31). This indicates that CD40 ligation may dominate signaling early in T cell-macrophage interaction but that other receptors may become involved later in the interaction.

Receptors other than CD40 that have been reported to signal macrophage function include CD23 (90,91), CD31 (92), CD38 (93), CD44 (94), CD45 (45,94), CD69 (95,96), and LFA-3 (94). The most abundant data is on CD23. CD23 is the low affinity Fc RII and thus is capable of binding complexes of antigen and IgE antibody. In addition, CD23 binds CD21 (97) and, according to one report, also binds CD11b and CD11c (98). Ligation of membrane CD23 on macrophages induces production of TNF-alpha, IL-6, and nitric oxide (97,99,100). Interestingly, ligation of CD21 on the macrophage membrane by soluble CD23 also has been reported to induce the production of TNF-alpha and IL-1 by macrophages (101,102). CD21 (90) and, under more restricted conditions, CD23 (103) have been reported to be expressed by activated but not by resting T cells. It is therefore possible that the CD23:CD21 receptor:ligand pair is involved in T cell-mediated signaling of some inflammatory macrophage functions. Ligation of CD40 on myeloid cells, endothelial cells, and fibroblasts can induce a wide range of functional activities which could contribute to essentially every aspect of cell-mediated inflammatory responses.