Recognition of altered self major histocompatibility complex molecules modulated by specific peptide interactions

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Abstract
Antigen‐specific and major histocompatibility complex (MHC)‐restricted recognition by the T cell receptor involves multiple structural contacts over a large molecular surface area. Using a human T cell clone specific for a rubella viral peptide restricted by subsets of HLA DR4 molecules, we identified structurally diverse combinations of peptide‐MHC complexes which were functionally equivalent for T cell recognition. Presentation of the rubella‐derived peptide on DR4 molecules with an E‐74 polymorphism triggered T cell recognition, as did presentation of a single amino acid‐substituted peptide in the context of the DR4 molecule which lacked the E‐74 site. Peptide binding and molecular modeling analysis indicates the structural and functional complementarity of T cell recognition for a specific amino acid side chain, whether contributed by the peptide or by the MHC molecule.