Normal human CD8+ T cell clones were co-isolated from the same culture wells as CD4+ T effector cell clones specific for myelin basic protein (MBP). Microcultures from which the CD8+ clones were isolated initially proliferated weakly to whole MBP and to an MBP peptide spanning residues 90–170. This pattern of response was similar to strongly proliferating wells that yielded CD4+ T cell clones specific for the 90–170 peptide. After repeated stimulation, however, no response to MBP or MBP 90–170 was detected, even though the number of cells increased after stimulation. Phenotyping and TCR analyses revealed the presence of two CD8+, CD4–. IL-2R+ T cell isolates that expressed a single Vβ2gene (Vβ217) that differed from the CD4+ isolates that uniformly expressed Vβ214. One of these CD8+ clones (C9) inhibited the antigen-driven proliferation of an autologous MBP 90–170 reactive clone but not an autologous clone specific for Herpes simplex virus (HSV). without affecting MHC non-resuicted mitogen responses of the same clones. Moreover, C9 did not inhibit heterologous CD4+ T cell clones specific for MBP 1–38 or 90–170. A culture supernatant of the CD8+ clone showed the same pattern but lower levels of inhibition. C9 had mild cytolytic activity when incubated at high ratios with an autologous MBP-specific CD4+ clone. Lysis was blocked completely by anti-MHC class I antibodies. but not by anti-MHC II antibodies. These data suggest that CD8+ T cells can recognize idiotypic determinants on CD4+ MBP-specific T cells, and raise the possibility that CDS+ T cells could participate in the normal regulation of potentially pathogenic autoreactive effector cells.