Increased severity of experimental autoimmune encephalomyelitis in rats tolerized as adults but not neonatally to a protective TCR V beta 8 CDR2 idiotope.

The ability of synthetic V region peptides to induce regulatory T cells and Abs in rodents and humans provides clear evidence that these idiotopes do not naturally induce tolerance. In this study, we investigated the ability of TCR V beta 8.2 peptides to experimentally induce specific T cell tolerance, as measured by loss of Ag-specific proliferation and delayed-type hypersensitivity responses, and by increased susceptibility 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 delayed-type hypersensitivity response and an inability to vaccinate against EAE after adult immunization with the tolerizing peptide. We further evaluated the contribution of naturally induced TCR-specific responses to EAE resistance induced by challenging neonatally or adult tolerized rats with myelin basic protein in adjuvant. The clinical course of EAE was not significantly altered in rats tolerized neonatally to V beta 8.2 peptides, but both the severity and incidence of mortality from EAE was increased in rats tolerized as adults with V beta 8.2 peptides conjugated to syngeneic splenocytes. These results demonstrate that V beta 8.2 peptides are tolerogenic as well as immunogenic. Moreover, the observation of different effects of neonatal vs adult tolerization on the course of EAE suggests either the emergence of additional protective idiotopes after neonatal tolerization and/or mechanistic differences 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 CDR2 idiotope in recovery from EAE.