A breach in tolerance of self antigens results from a dysregulation of mechanisms that protect against autoimmunity. Different subsets of T cells may contribute to this balance by crossregulating each other. In this project we propose to examine whether manipulation of antigen presentation of major histocompatibility complex (MHC)- encoded class I responsive cells will influence the phenotype of T helper cells. Using gene therapy, peptides encoded by plasmid DNA will be selectively loaded onto MHC class I complexes in the absence of class II-restricted peptides. A peripheral T cell response will then be initiated by similarly introducing ectopic costimulator molecules at the same site of injection. The peptides selected for study are derivations of a well described cytotoxic T lymphocyte epitope that have been previously reported as having partial agonist or antagonist properties to T cell clones reactive to the original peptide. Preferentially prepriming the CD8+ compartment may establish conditions that influence the later response of the CD4+ compartment when the animals are challenged with the whole protein in vivo. Priming with a peptide from an unmutated antigen may not effect the phenotype of the subsequent CD4+ response, which would suggest that these compartments can operate concordantly in their responses. By changing the peptide ligand and presumably the avidity of the interaction with different T cell populations a spectrum of different effects of one compartment on the other in vivo could be induced. The effect of priming with an altered peptide ligand may not be directly measurable and be indirectly detectable by a change in the natural response to a subsequent protein challenge. Treatment of animals with this form of therapy before or after antigenic challenge of a known protein can be suppressed then this schema can be readily adapted to situations where a defined element is being introduced into the immune system. The ultimate goal is to develop a safe and effective means of aborting a deleterious autoimmune response.