Vaccination of rodents with subpathogenic doses of autoreactive T cells specific for antigens mediating autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) will protect against subsequent induction of the diseases. This protective effect has been shown to be associated with the activation of regulatory T cells specific for encephalitogenic T cells or for the T-cell receptor (TCR) of encephalitogenic T cells. This proposal will continue my previous work on EAE by determining what factors on the encephalitogenic T cells determine whether or not the cells possess vaccinating activity. One of the major questions to be addressed is why, among encephalitogenic T-cell lines that share common TCR elements (e.g. , TCR Vbeta8, which is involved in the vaccinating activity against EAE), do only some lines possess vaccinating activity? Besides determining the mechanism(s) by which encephalitogenic T cells activate regulatory cells possessing suppressive activity in EAE, I will also attempt to correlate the activity of distinct regulatory cell populations (clonotypic and nonclonotypic) with encephalitogenic T cells specific for different myelin basic protein (MBP) epitopes (e.g., residues 68-88 and 87-99). These investigations will profit from a unique rat EAE model developed in my laboratory, in which the vaccinating activity of encephalitogenic T cells can be readily tested in vivo. A panel of encephalitogenic T-cell lines and the T-cell hybrids directed to different epitopes of MBP, as well as regulatory T-cell lines that protect against encephalitogenic cells, should also facilitate this research. The information gained from these studies will improve understanding of (i) the heterogeneous properties of individual encephalitogenic T-cell clones; (ii) the repertoire of encephalitogenic T cells; and (iii) the role of regulatory cells and the immunoregulatory cascade in the process of autoimmune diseases such as EAE. These studies represent the first step toward using EAE-specific molecules to manipulate regulatory cells to therapeutic advantage.