Functional and structural basis of T cell recognition in autoimmune gastritis: mapping of autoantigenic peptides of the α-chain of the H/K ATPase and X-ray structure of the I-Ad/peptide complexes (106.25)

Abstract

Abstract We have previously reported the development of mouse models of autoimmune gastritis in which BALB/c mice expressing transgenic αβ TCR, designated A23 and A51, spontaneously develop acute Th1-mediated high-penetrance and chronic Th2-mediated low penetrance forms of the disease, respectively. Using an array of synthetic mutated peptides in functional and MHC II-binding assays, we now report the core peptides recognized by each of these TCR. A23 recognizes H/K ATPase residues 633-641 (AKAIAASVG) and A51 sees 892-900 (CVGLRPQWE), both exhibiting a canonical 1, 4, 6, 9 I-Ad -binding motif. To extend these findings, we determined the X-ray crystallographic structure of complexes of I-Ad with both covalent and non-covalent peptides that stimulate the A51 TCR, and used these structures to generate a molecular model of the A23-stimulating peptide/I-Ad complex. The structural identification of peptide anchor residues in individual I-Ad binding pockets and of solvent exposed side chains as T cell epitopic residues readily explains T cell proliferation data and I-Ad/peptide off-rate measurements of the large panel of truncated, chimeric, and alanine or glycine-substituted synthetic peptides. The first structure of I-Ad in complex with an autoimmune peptide offers new insight in the general question of the structural basis of responses to self antigens.