ANTIGEN PRESENTATION IN UVEITIS

Experimental autoimmune uveoretinitis (EAU) is not only a valuable mod el for human inflammatory eye diseases, it is also a useful system for studying many aspects of immunobiology. One such aspect is self/non-s elf discrimination, the ability of the immune system to tolerate self molecules while responding aggressively to foreign antigens. Our labor atory has used EAU to investigate the mechanisms of T cell tolerance t o retinal S-antigen (S-Ag). Several mechanisms have been proposed to m aintain T cell tolerance to autoantigens, including clonal deletion an d clonal anergy. As immunisation with S-Ag or pathogenic peptides acti vates uveitogenic T cells, tolerance to this autoantigen cannot be due to clonal deletion. Nevertheless, tolerance acts to keep these existi ng autoreactive T cells in a naive, or innocuous state. Here me sugges t a novel mechanism - low-affinity occupancy of the autoantigen-specif ic T cell receptor (TCR) by self-antigen - that may act in concert wit h the well-known,ia mechanisms to maintain tolerance to S-Ag in the LE W rat. This model differs from clonal energy in that the missing antig en-presenting cell (APC) activity is not a co-stimulatory function but a TCR co-ligand that increases the avidity of the interaction between the TCR and its peptide-major histocompatibility complex (MHC) ligand . In the absence of this co-ligand only partial signals are generated through the TCR, leading to incomplete T cell activation. This model w as deduced from experiments with T cell lines and hybridomas specific for S-Ag, which showed that: (1) autoreactive T cells required a novel APC function, (2) this novel function was necessary to provide comple te TCR engagement, and (3) activation of autoreactive T cells was rest ricted to specific APC.