SUBTLE CONFORMATIONAL-CHANGES INDUCED IN MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II MOLECULES BY BINDING PEPTIDES

Intracellular trafficking of major histocompatibility complex (MHC) cl ass II molecules is characterized by passage through specialized endoc ytic compartment(s) where antigenic peptides replace invariant chain f ragments in the presence of the DM protein. These changes are accompan ied by structural transitions of the MHC molecules that can be visuali zed by formation of compact SDS-resistant dimers, by changes in bindin g of mAbs, and by changes in T cell responses. We have observed that a mAb (25-9-17) that is capable of staining I-Ab on the surface of norm al B cells failed to interact with I-Ab complexes with a peptide deriv ed from the E-alpha chain of the I-E molecule but bound a similar cova lent complex of I-Ab with the class IT binding fragment (class LI-asso ciated invariant chain peptides) of the invariant chain. Moreover, 25- 9-17 blocked activation of several I-Ab-reactive T cell hybridomas but failed to block others, suggesting that numerous I-Ab-peptide complex es acquire the 25-9-17(+) or 25-9-17(-) conformation. Alloreactive T c ells were also able to discriminate peptide-dependent variants of MHC class II molecules. Thus, peptides impose subtle structural transition s upon MHC class II molecules that affect T cell recognition and may t hus be critical for T cell selection and autiommunity.