We have investigated whether the normal immune system contains T cells that are able to recognize T cell receptor (TcR) determinants of autologous autoantigen‐specific T cells. The T cell clone HW. BP3, specific for myelin basic protein (MBP) was isolated from a healthy donor. HW.BP3 is restricted by HLA‐DR2a, and reacts to human MBP 139‐153. The expressed α β TcR genes of HW.BP3 were cloned and sequenced, and the sequences analyzed for potential T cell epitopes. Two synthetic peptides, one from the VDJβ junctional (β1) and one from theVβ region (β2) of the TcR of IIW.BP3, were used to select four TcR peptide‐specific T cell lines from the donor of HW.BP3. All anti‐TcR lines had the phenotype CD3⁺/CD4⁺/HLA‐DR⁺/CD25⁻/CD45RO⁻, and recognized the antigen in the context of HLA‐DR. Three anti‐TcR lines, which had been selected for reactivity to peptide pi, recognized exclusively this peptideβ1, restricted by HLA‐DR2b. One anti‐TcR line, selected for peptide (β2, responded to both peptides pi and P2 when presented by autologous blood mononuclear cells, but not by HLA‐DR2a‐ or HLA‐DR2b‐transfected L cells.

All TcR peptide‐specific T cell lines were efficiently cytotoxic. They specifically lysed autologous macrophages or HW.BP3 line cells in the presence of exogenous peptide antigen. In contrast, HW.BP3 did not present endogenous TcR peptides to the anti‐TcR lines. The results demonstrate that the normal human immune system contains not only autoantigen‐specific T cells, but also T cells that recognize antigenic determinants of autologous autoreactive TcR.