COCULTURE OF TCR PEPTIDE-SPECIFIC T-CELLS WITH BASIC PROTEIN-SPECIFICT-CELLS INHIBITS PROLIFERATION, IL-3 MESSENGER-RNA, AND TRANSFER OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

TCR peptides, namely V beta 8.2-39-59 or the minimal idiotope, V beta 8-44-54, can treat experimental autoimmune encephalomyelitis (EAE) in Lewis rats, presumably by activating naturally induced TCR peptide-spe cific T cells that arise in response to the focused appearance of V be ta 8.2(+) encephalitogenic T cells. The purpose of the present study w as to evaluate the mechanisms by which TCR peptides inhibit EAE. We fo und that treatment of EAE with the V beta 8.2-39-59 peptide did not in duce any evidence of DNA fragmentation (apoptosis) in spinal cord cell s isolated from clinically well rats, implicating a regulatory rather than a deletional mechanism. TCR peptide-specific T cell lines failed to inhibit EAE induced by already activated BP-specific T cells when t he two T cell specificities were co-injected. However, coculturing the encephalitogenic T cells in the presence of the regulatory T cells du ring the activation step before transfer almost completely inhibited t he induction of EAE. Inhibition could be induced by direct contact bet ween the two cell types or by soluble factors produced in a transwell system, but was greatly enhanced when soluble V beta 8.2-39-59 peptide was used to optimally activate the regulatory T cells. The inhibition was regulatory cell dose dependent, and was reflected in vitro by red uced proliferation response and mRNA production for IL-3, and to a les ser extent, IFN-gamma and IL-2. These results indicate that regulation induced by TCR peptides involves cell-cell interactions that lead to the production and release of soluble factors that locally inhibit the activation of encephalitogenic T cells expressing MHC-bound idiotopes of the target V beta-chain, and possibly ''bystander'' specificities expressing different V beta-chains.