Functionally distinct subsites on a class II major histocompatibility complex molecule

Abstract

Mature T lymphocytes are activated by recognition of the combination of foreign protein antigen and membrane products of the major histocompatibility complex (MHC)¹. Studies of peptide antigen binding to detergent-solubilized class II MHC molecules (Ia) have established that peptide–Ia interaction occurs in the absence of the T-cell receptor and varies according to allele-specific features of Ia molecules^2–4. The residues of immunogenic peptides thus contribute to two largely independent functions — the control of association with Ia molecules and the determination of the specificity of T-cell receptor binding^5,6. Two analogous and potentially independent functional sites have been postulated for Ia molecules⁷— a region that controls binding to peptides and a region that interacts with T-cell receptors. Here we present evidence from functional analysis of recombinant class II molecules that these two postulated functional regions of Ia molecules do exist and can be independently manipulated, consistent with our recent demonstration of the segmental nature of Ia molecule structure-function relationships^8.