T cells respond to environmental or experimentally introduced foreign antigens by recognizing degraded peptides associated with molecules of the major histocompatibility complex (MHC. Recognition of self antigen molecules in autoimmunity involves a similar process. Recent studies with two different model systems in rats - one involving T cells which cause graft-versus-host (GVH) disease, and the second involving T cells reactive to myelin basic protein that cause experimental allergic encephalomyelitis (EAE) - have demonstrated that disease causing T cell populations are themselves very effective vaccines for inducing immune resistance in these two disease models. In both cases, the immune resistance mechanism depends on regulatory T cells reactive to antigen specific receptors on disease causing T cells. There are two questions that arise from these experimental findings: (i) are T cell antigen receptors (TCR) themselves processed and recognized as self-peptides associated with MHC? and (ii) is recognition of processed TCR part of a fundamental mechanism of immune regulation? Recent demonstrations that synthetic peptides corresponding to the variable elements of T cell receptors on EAE causing clones are effective vaccines against active disease support the notion that receptors on disease-causing T cells are processed and can stimulate an immunoregulatory response. If the EAE and GVH resistance models operate by similar mechanisms, then it should be possible to identify TCR peptides which are effective vaccines against active GVH disease. Accordingly, we outline here a series of studies designed to: (i) identify, by PCR and direct sequencing procedures, the variable gene segments of T cell receptors employed in alloreactive T cell subpopulations including """"""""mono-Vbeta"""""""" T cell populations selected with appropriate monoclonal antibodies (ii) prepare synthetic peptides presumed to correspond to natural TCR peptides and test their efficacy as vaccines in producing specific resistance to GVH disease; and (iii) explore the immune status of animals immunized with selected TCR peptides or """"""""mono-Vbeta"""""""" T cell populations, and the fate of T cells bearing the corresponding native TCR molecules.
