[Frontiers in Bioscience 2, d197-206, May 1, 1997]

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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


Research over the past decade has only begun to unravel the complex interactions between T cells and macrophages that are involved in the pathogenesis of cell-mediated inflammatory diseases such as multiple sclerosis. The cellular infiltrates of active sclerotic lesions include CD4+ T cells (Th1 with some Th0 and Th2), CD8+ T cells, and macrophages (microglia and monocytes) (1-8). The types of cells present reflect the state of progression of the inflammatory lesion. Macrophages play critical accessory, inflammatory, and effector roles in this non-septic T cell-mediated inflammatory disease (5-9) and tend to be present throughout the inflammatory process. The development of a cell-mediated response is currently hypothesized to depend on the differentiation of interferon (IFN)-gamma producing Th1 cells from activated Th0 precursors (10,11). The production of interleukin (IL)-12 by macrophages clearly plays an important role in the maturation of Th1 cells (10). Upon maturation, these Th1 cells, as well as inflammatory CD8+ cells, both of which produce IFN-gamma and tumor necrosis factor (TNF)-alpha/beta, play a dominant role in macrophage activation and pathogenesis of the inflammatory lesion (1,3,12-15). In contrast, IL4/IL10-producing T cells are hypothesized to play a role in down-regulation of the inflammatory response (1,3,16). It is these "type 2" CD8+ cells that appear to be active in the cellular infiltrate of sclerotic lesions that are in remission (1,3).

In addition to the many roles of T cell-derived cytokines in stimulation and inhibition of macrophage function (13), research over the last few years has demonstrated that the critical triggering event in activation of macrophage cytokine production and effector function is contact-dependent signaling during T cell:macrophage adhesion (17-24). Substantial research emphasis was placed on CD40 as a mediator of contact-dependent signaling of macrophages. CD40 ligation has been reported to contribute to the induction of accessory molecules such as CD80 and CD86 (25-27), to the induction of inflammatory cytokines and chemokines (27-29), and to the induction of nitric oxide generation (24) and metalloproteinase secretion (30). However, the observation that T cells from CD40L-deficient mice are capable of contact-dependent signaling of macrophages (31) establishes that membrane-anchored receptor:ligand pairs other than CD40:CD40L can be involved in T cell signaling of macrophages. In the following sections, we try to provide a succinct account of T cell signaling of macrophages which, although brief and simplified for the sake of clarity, emphasizes the complexity of the cascading cell-cell interactions involved in a relapsing inflammatory autoimmune disease.