Is there restricted T cell receptor usage in autoimmune disease?

Abstract

Tolerance to self-antigens is thought to be acquired during ontogeny and accomplished by a combination ofclonal deletion and anergy of self reactive T cells. Autoimmunity develops following a breakdown in the mechanisms maintaining selftolerance when autoreactive T cells that are present in all individuals become activated. Since T cells recognize antigen in the context of class I or class II MHC molecules, several therapeutic approaches are theoretically possible to try to ameliorate or prevent autoimmune pathology. If the autoantigen is known, there is the possibility of designing peptides that would prevent T cell interaction with the autoantigen or tolerize the autoreactive T cell. If the critical restriction element is known, antibodies to these MHC molecules may be used to block the immune response to the antigen. Finally, if there is evidence of restricted T cell receptor (TCR) usage, antibodies may be employed to eliminate these T cells specifically, or vaccination protocols may be developed to specific T cells bearing these receptors. The possibility of specifically inhibiting T cells involved in autoimmune pathology while sparing those responding to wholly exogenous antigens is an attractive therapeutic option. Some experiments have implied that there might be some restriction of TCR usage by T cells involved in autoimmune pathology. These studies showed that it was possible to 'vaccinate' animals against the experimental induction of autoimmune disease using glutaraldehyde-fixed autoreactive T cell clones (Ben-Nun, Wekerle & Cohen, 1981). Concrete evidence for restricted Vfl usage by autoreactive T cells came from studies of experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis, which convincingly demonstrated that the T cell initiating this disease utilized V/38.2 in their TCR (Acha-Orbea et al., 1988; Acha-Orbea, Steinman & McDevitt, 1989). Following on from these observations in mice a similar situation was shown to exist for rat EAE (Heber Katz & Acha-Orbea, 1989); and EAE in rats was shown to be prevented not just by vaccination with inactivated T cell clones but also by immunization with synthetic peptides of sequences found in CDR2 and CDR3 TCR y regions (Vandenbark, Hashim & Iffner, 1989). Additional evidence for restricted TCR usage emerged from studies of collagen-induced arthritis in mice and the spontaneous insulin-dependent diabetes ofNOD mice. Genetic studies suggested that Vf6 bearing T cells may be necessary for the induction of arthritis in mice (Haqqi et al., 1988; Banerjee et al., 1989). However, the interpretation of the data has been