Uveitogenic T lymphocytes in the rat: pathogenicity vs. lymphokine production, adhesion molecules and surface antigen expression

A possible correlation between the pathogenicity of autoimmune T cells and their lymphokine production, expression of functional adhesion molecules and expression of some surface antigens was examined. We used four retinal antigen-specific Lewis rat T cell lines and sublines: one specific to the major pathogenic epitope of the human retinal soluble antigen (S-Ag; residues 337-356), and three specific to the major pathogenic epitope of the bovine interphotoreceptor retinoid binding protein (IRBP; residues 1177-1191). The lines have different degrees of uveitogenicity, from highly pathogenic to nonpathogenic. All four T cell lines produced roughly equivalent amounts of interferon-gamma, lymphotoxin/tumor necrosis factor (TNF alpha/beta), interleukin-3, interleukin-6 and transforming growth factor-beta. Interleukin-4 activity could not be detected. The lines also expressed similar levels of functional adhesion molecules, as measured by binding to cultured rat aorta endothelial cells. The nonpathogenic subline, however, was the lowest responder to antigenic stimulation with respect to proliferation and interleukin-2 production. Examination of cell surface antigens showed that in contrast to the other lines, the majority of cells in the nonpathogenic subline lacked detectable expression of CD4. No difference was found in the level of expression of the IL-2 receptor and T cell antigen receptor among the four lines. Because CD4 is the restricting element in these lines, reduced CD4 expression in the nonpathogenic subline may at least partially explain its poor response in vitro to antigenic stimulation. All three attributes could be connected to lack of pathogenicity of this line in vivo. These results support the contention that class II-restricted recognition of autoantigen within the neuroretina by uveitogenic T lymphocytes must occur as an initial step in the pathogenesis of EAU. A defect in this step will preclude pathogenesis regardless of some other functional attributes possessed by effector T cells, such as production of inflammatory lymphokines and expression of adhesion molecules.