Subtle Conformational Changes Induced in Major Histocompatibility Complex Class II Molecules by Binding Peptides

• Published in: Proceedings of the National Academy of Sciences - PNAS 1998-08, Vol.95 (17), p.10094-10099
• Main Authors: Chervonsky, Alexander V., Medzhitov, Ruslan M., Denzin, Lisa K., Barlow, Avlin K., Alexander Yu. Rudensky, Janeway, Charles A.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies; Antibodies, Monoclonal; Antigens, Differentiation, B-Lymphocyte - genetics; Antigens, Differentiation, B-Lymphocyte - metabolism; B lymphocytes; B-Lymphocytes - immunology; Biological Sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell lines; Cell Membrane - immunology; Dimerization; Dimers; Histocompatibility Antigens Class II - chemistry; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - metabolism; Hybridomas; L cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; Molecules; Peptides; Protein Binding; Protein Conformation; Reactivity; Splenocytes; T lymphocytes; T-Lymphocytes - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.17.10094

Intracellular trafficking of major histocompatibility complex (MHC) class II molecules is characterized by passage through specialized endocytic compartment(s) where antigenic peptides replace invariant chain fragments in the presence of the DM protein. These changes are accompanied by structural transitions of the MHC molecules that can be visualized by formation of compact SDS-resistant dimers, by changes in binding of mAbs, and by changes in T cell responses. We have observed that a mAb (25-9-17) that is capable of staining I-Abon the surface of normal B cells failed to interact with I-Abcomplexes with a peptide derived from the Eαchain of the I-E molecule but bound a similar covalent complex of I-Abwith the class II binding fragment (class II-associated 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 complexes acquire the 25-9-17+or 25-9-17-conformation. Alloreactive T cells were also able to discriminate peptide-dependent variants of MHC class II molecules. Thus, peptides impose subtle structural transitions upon MHC class II molecules that affect T cell recognition and may thus be critical for T cell selection and autiommunity.