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Acetylcholine Receptor Peptide Recognition in HLA DR3-Transgenic Mice: In Vivo Responses Correlate with MHC-Peptide Binding¹

Raghavanpillai Raju^2,*, Edward G. Spack^3, and Chella S. David

^* Division of Immunology, St. Luke’s Medical Center, Milwaukee, WI 53215; Department of Immunology, Corixia Corp. (formerly Anergen Inc.), Redwood City, CA 94010; and Department of Immunology, Mayo Medical School, Rochester, MN 55905

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

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