Structural analysis of two HLA-DR-presented autoantigenic epitopes: crucial role of peripheral but not central peptide residues for T-cell receptor recognition

Specific and major histocompatibility complex (MHC)-restricted T-cell recog nition of antigenic peptides is based on interactions of the T-cell recepto r (TCR) with the MHC alpha helices and solvent exposed peptide residues ter med TCR contacts. In the case of MHC class II-presented peptides, the latte r are located in the positions p2/3, p5 and p7/8 between MHC anchor residue s. For numerous epitopes, peptide substitution studies have identified the central residue p5 as primary TCR contact characterized by very low permiss iveness for peptide substitution, while the more peripheral positions gener ally represent auxiliary TCR contacts. In structural studies of TCR/peptide /MHC complexes, this has been shown to be due to intimate contact between t he TCR complementarity determining region (CDR) three loops and the central peptide residue. We asked whether this model also applied to two HLA-DR pr esented epitopes derived from an antigen targeted in type I diabetes. Large panels of epitope variants with mainly conservative single substitutions w ere tested for human leukocyte antigen (HLA) class II binding affinity and T cell stimulation. Both epitopes bind with high affinity to the presenting HLA-DR molecules. However, in striking contrast to the standard distributi on of TCR contacts, recognition of the central p5 residue displayed high pe rmissiveness even for non-conservative substitutions, while the more periph eral p2 and p8 TCR contacts showed very low permissiveness for substitution . This suggests that intimate TCR interaction with the central peptide resi due is not always required for specific antigen recognition and can be comp ensated by interactions with positions normally acting as auxiliary contact s. (C0 2001 Elsevier Science Ltd. All rights reserved.