The T cell receptor (TCR) is critical in defining the specificity component of T cell function. In turn, T cell-specific responsiveness is important in maintaining immune surveillance and establishing immunologic memory against invading pathogens. Unfortunately, this defensive mechanism may also direct itself against self antigens and may result in T cell- mediated autoimmune disease. One long term goal of this study is to gain better understanding of TCR-specific reactivity, particularly as it pertains to autoreactivity. We wish to pursue this using the T cell mediated autoimmune disease model, experimental autoimmune encephalomyelitis (EAE). EAE can be actively induced by immunization with components of the myelin sheath such as myelin basic protein (BP) or proteolipid protein (PLP) and can also be induced by passive transfer of T cells specific for encephalitogenic peptides of BP or PLP. TCR V gene utilization in EAE- inducing, BP-specific T cells has been analyzed to different extents in rats and mice and appears to be restricted. In the Lewis rat model of EAE, T cells specific for BP72-89 demonstrate dominant V-beta-8.2 expression in association with a CDR3 motif, perhaps identifying residues important in contacting MHC-bound peptide. The involvement of these and other V-beta- 8.2 CDR residues in peptide/MHC recognition will be directly tested in this proposal. In addition, because the characterization of V-alpha expression in rat EAE has been relatively limited, the role of V-alpha in EAE will be further investigated here as well. Biased V gene usage in EAE has led to several experimental therapies which target the surface-expressed TCR. The EAE-associated V-beta CDR3, formed by junctional regions between V-beta and D-beta, as well as D-beta and J- beta segments, may not only play a significant role in antigen/MHC recognition, but may constitute a unique marker for encephalitogenic T cells. The generation of monoclonal antibodies which include recognition of this marker would be extremely useful for detecting encephalitogenic T cells within a heterogeneous population prior to disease onset. In addition, these monoclonal antibodies may have potential therapeutic value.
