INCREASED SEVERITY OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN RATS TOLERIZED AS ADULTS BUT NOT NEONATALLY TO A PROTECTIVE TCR V-BETA-8CDR2 IDIOTOPE

The ability of synthetic V region peptides to induce regulatory T cell s and Abs in rodents and humans provides clear evidence that these idi otopes do not naturally induce tolerance. In this study, we investigat ed the ability of TCR V beta 8.2 peptides to experimentally induce spe cific T cell tolerance, as measured by loss of Ag-specific proliferati on and delayed-type hypersensitivity responses, and by increased susce ptibility to experimental autoimmune encephalomyelitis (EAE). We found that both neonatal and adult exposure to V beta 8.2-39-59 or V beta 8 -44-54 peptides could induce efficient T cell tolerance, resulting in a significant inhibition of peptide-specific proliferative responses. In addition, neonatal tolerance resulted in a partial reduction in del ayed-type hypersensitivity response and an inability to vaccinate agai nst EAE after adult immunization with the tolerizing peptide. We furth er evaluated the contribution of naturally induced TCR-specific respon ses to EAE resistance induced by challenging neonatally or adult toler ized rats with myelin basic protein in adjuvant. The clinical course o f EAE was not significantly altered in rats tolerized neonatally to V beta 8.2 peptides, but both the severity and incidence of mortality fr om EAE was increased in rats tolerized as adults with V beta 8.2 pepti des conjugated to syngeneic splenocytes. These results demonstrate tha t V beta 8.2 peptides are tolerogenic as well as immunogenic. Moreover , the observation of different effects of neonatal vs adult tolerizati on on the course of EAE suggests either the emergence of additional pr otective idiotopes after neonatal tolerization and/or mechanistic diff erences in the two tolerance-inducing protocols. Most importantly, the enhancement of clinical EAE in rats tolerized as adults with V beta 8 .2 peptides provides evidence for an innate regulatory role of the CDR 2 idiotope in recovery from EAE.