|[Frontiers in Bioscience 2, d197-206, May 1, 1997]|
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
The role of contact-dependent signaling in the development of experimental allergic encephalomyelitis has been shown dramatically using transgenic B10.PL mice expressing the T cell receptor reactive with the encephalitogenic peptide (Ac1-11) of myelin basic protein. Transgenic CD40L-deficient mice, unlike +/+ transgenic mice, do not develop acute experimental allergic encephalomyelitis upon immunization with Ac1-11 (104). This nonresponsiveness was ascribed to the inability of CD40L-deficient T cells to induce CD80 expression on dendritic cells. The adoptive transfer of CD80-positive accessory cells into CD40L-deficient mice restored their ability to respond to antigen and to develop experimental allergic encephalomyelitis. This indicates that, unless an undiscovered second ligand for CD40 exists, T cells are capable of driving the inflammatory process by CD40-independent receptor:ligand and/or cytokine signaling.
Although the above studies with transgenic CD40L-deficient mice suggest that CD40 ligation is not required for the development of sclerotic lesions once the CD80 costimulus is provided, studies with normal animals indicate that CD40:CD40L
interactions play a significant role throughout the inflammatory process. Administration of anti-CD40L antibody as late as 7-9 days after immunization of SJL mice with encephalitogenic peptide reduced the extent and severity of lesions by more than 50% (6). This is not surprising because CD40:CD40L interactions are known to play many roles in cell-mediated inflammatory responses, including stimulation of expression of adhesion and homing molecules on vascular endothelium, stimulation of chemokine and inflammatory cytokine production, stimulation of the production of IL-12, which is critical for maturation of the inflammatory Th1 subset, and stimulation of fibroblasts (105) (Table 1). Several of the above activities are critical for the development of experimental allergic encephalomyelitis. VCAM-1 plays a critical role in the inflammatory process of experimental allergic encephalomyelitis (106); ligation of CD40 on endothelial cells induces VCAM-1 expression (107). Blockade of CD80 expression has been shown to prevent clinical relapses and chronicity of experimental allergic encephalomyelitis (108-110); antibody blockade of CD40:CD40L interactions completely blocks T cell contact-induction of CD80 expression (25). Since neither IL-10 nor TGF-beta appear to down-regulate CD80 expression (52,53), the down-regulation of CD40L, and hence CD40L stimulation of CD80 expression, may therefore be a pivotal event in the shift from inflammatory to anti-inflammatory activities in the sclerotic lesion.