Myasthenia gravis is a human disease caused by an autoimmune response against the nicotinic acetylcholine receptor (AcChoR). Since the molecular structure of AcChoR is well known, myasthenia gravis is an excellent system for studying the recognition of a complex membrane antigen in the human immune system. Human T-helper (TH) cell lines reactive to the AcChoR were isolated from four myasthenic patients by selection with native AcChoR from Torpedo californica. The selected TH cells could efficiently recognize native and fully denatured AcChoR. The vast majority of the TH-stimulating AcChoR epitopes were located on the denatured alpha subunit of AcChoR. Antibody competition experiments using a panel of rat anti-AcChoR monoclonal antibodies showed that 39-45% of the autoantibodies present in the sera of these same patients bound to the conformation-sensitive "main immunogenic region" (MIR), also located on the alpha subunit. However, AcChoR-induced stimulation of the T cells could not be inhibited with up to 20-fold molar excess of different rat anti-MIR monoclonal antibodies. These results suggest that the Torpedo AcChoR alpha subunit contains conformation-insensitive epitopes that play a role in the autosensitization of TH cells and that seem to be physically separated from the MIR. The specificity of the TH cell response may contribute to directing the B-cell response to other alpha-subunit determinants, such as the MIR itself.