Encephalitogenic T cells of both PL/J mice and Lewis rats are restricted by TCR Vβ8.2, although they recognize different epitopes in the myelin basic protein (MBP) molecule. We sought the presence of a cross-reactive idiotope (Id) in encephalitogenic T cells of Lewis rats by examining the effects of mAb F30 anti-Id, which recognized a TCR Id in PL/JT cells, on the encephalitogenic LR88L1 cell line derived from Lewis rats and specific for guinea pig MBP peptide 68-88. The LR88L1 cells were I-A restricted and TCR Vβ8.2+, and their proliferation and secretion of IL-2 and TNF-α induced by guinea pig MBP peptide 68-88 was inhibited by mAb F30 anti-Id. As shown by FACS analysis and by immunoprecipitation of TCR from radiolabeled LR88L1 cell lysates, the F30 anti-Id bound to the TCRs of Vβ8.2+ LR88L1 cells. In addition, TCR sequences in the F30+ population of LR88L1 cells were the same as those of encephalitogenic Lewis rat T cells published previously. The F30+ LR88L1 cells showed reduced encephalitogenicity compared with F30- or unsorted LR88L1 cells. The mechanism for this reduction by anti-Id probably resulted from the induction of anergy, in that IL-2 reversed the anti-Id effect. The control LR99L1 T cell line, also encephalitogenic, but specific for MBP peptide 87-99 and I-E, and not TCR Vβ8.2 restricted, failed to react with, or have its cytokine secretion inhibited by, mAb F30 anti-Id. These results demonstrate an interspecies cross-reactive Id expressed in common by encephalitogenic T cells that share a similar TCR, although they differ in MBP epitope specificity. These findings suggest that a common Id restricted by TCR, but less restricted by the encephalitogenic epitope, and recognized by the Id-bearing autoreactive T cells may represent an immunotherapeutic approach for treating autoimmune demyelinating diseases.