During the evolution of the autoimmune response to myelin basic protein (MBP), at least two distinct lymphocyte populations arise, one that is specific for determinants within the protein antigen and another that is specific for the receptors displayed by the antigen‐specific lymphocytes themselves. The T‐cell receptor (TCR)‐specific lymphocytes appear to oppose the action of the pathogenic effector cells, which predominantly utilize the TCR Vβ8.2 gene segment. We will discuss our work suggesting that both CD4 and CD8 cells specific for different TCR determinants on the Vβ8.2 chain are involved in the regulation of MBP‐specific CD4 T cells mediating experimental autoimmune encephalomyelitis. We suggest that a crucial balance between the effectors and regulators is decisive for the clinical manifestation of autoimmunity. © 1996 Wiley‐Liss, Inc.