Antigen presentation in uveitis.
Experimental autoimmune uveoretinits (EAU) is not only a valuable model for human inflammatory eye diseases, it is also a useful system for studying many aspects of immunobiology. One such aspect is self/non-self discrimination, the ability of the immune system to tolerate self molecules while responding aggressively to foreign antigens. Our laboratory has used EAU to investigate the mechanisms of T cell tolerance to retinal S-antigen (S-Ag). Several mechanisms have been proposed to maintain T cell tolerance to autoantigens, including clonal deletion and clonal anergy. As immunisation with S-Ag or pathogenic peptides activates uveitogenic T cells, tolerance to this autoantigen cannot be due to clonal deletion. Nevertheless, tolerance acts to keep these existing autoreactive T cells in a naive, or innocuous state. Here we suggest a novel mechanism--low-affinity occupancy of the autoantigen-specific T cell receptor (TCR) by self-antigen--that may act in concert with the well-known mechanisms to maintain tolerance to S-Ag in the LEW rat. This model differs from clonal anergy in that the missing antigen-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 was 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 complete TCR engagement, and (3) activation of autoreactive T cells was restricted to specific APC.
Prasad
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SA
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Gregerson
D S
DS
D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D004195:Disease Models, Animal; D007108:Immune Tolerance; D051381:Rats; D011917:Rats, Inbred Lew; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015866:Uveitis, Posterior / Q000276:immunology*
D001324:Autoantigens; D011948:Receptors, Antigen, T-Cell