No immunodominant T‐cell epitopes have yet been reported in the human acetylcholine receptor (AChR), the target of the pathogenic autoantibodies in myasthenia gravis (MG). We have selected and characterized T cells from MG patients by restimulation in culture with recombinant human AChR α, γ, and ε subunits; the γ and ε distinguish the fetal and adult AChR isoforms, respectively. We obtained clones specific for the ε, rather than the α or γ, subunit in 3 of the first 4 early‐onset MG cases tested. They all responded to peptide ε201–219 and to low concentrations of adult but not fetal AChR. Moreover, although using different T‐cell receptor genes, they were all restricted to HLA‐DR52a (DRB3*0101), a member of the strongly predisposing HLA‐A1‐B8‐DR3 haplotype. This apparently immunodominant ε201–219 epitope (plus DR52a) was also recognized by clones from an elderly patient whose MG had recently been provoked by the drug D‐penicillamine. In all 4 cases, however, the serum antibodies reacted better with fetal than adult AChR and may thus be end products of determinant spreading initiated by adult AChR‐specific T cell responses. Furthermore, as these T cells had a pathogenic Th1 phenotype, with the potential to induce complement‐activating antibodies, they should be important targets for selective immunotherapy. Ann Neurol 1999;45:224–231