Acetylcholine receptor peptide recognition in HLA DR3-transgenic mice: In vivo responses correlate with MHC-peptide binding

HLA DR3 is an MHC molecule that reportedly predisposes humans to myasthenia gravis (MG). Though MG is an Ab-mediated autoimmune disease, CD4(+) T cell s are essential for the generation of high-affinity Abs; hence the specific ities of autoreactive CD4(+) T cells are important. In this study we report the HLA DR3-restricted T cell determinants on the extracellular region seq uence of human acetylcholine receptor a subunit. We find two promiscuous de terminants on this region 141-160 and 171-190 as defined by their immunogen icity in HLA DR3-, HLA DQ8-, and HLA DQ6-transgenic mice in the absence of endogenous mouse class II molecules. We also studied the minimal determinan ts of these two regions by truncation analysis, and the MHC binding affinit y of a set of overlapping peptides spanning the complete sequence region of human acetylcholine receptor a subunit. One of the peptide sequences stron gly immunogenic in HLA DR3-transgenic mice also had the highest binding aff inity to HLA DR3. Identification of T cell determinants restricted to an MH C molecule known to predispose to MG may be an important step toward the de velopment of peptide-based immunomodulation strategies for this autoimmune disease.