Conformational heterogeneity of MHC class II induced upon binding to different peptides is a key regulator in antigen presentation and epitope selection

Abstract

T cells bearing alphabeta receptors recognize antigenic peptides bound to class I and class II glycoproteins encoded in the major histocompatibility complex (MHC). Cytotoxic and helper T cells respond respectively to peptide antigens derived from endogenous sources presented by MHC class I, and exogenous sources presented by MHC II, on antigen presenting cells. Differences in the MHC class I and class II structures and their maturation pathways have evolved to optimize antigen presentation to their respective T cells. A main focus of our laboratory is on efforts to understand molecular events in processing of antigen for presentation by MHC class II. The different stages of MHC class II-interactions with molecular chaperons involved in folding and traffic from the ER through the antigen-loading compartments, peptide exchange, and transport to the cell surface have been investigated. Through intense research on biophysical and biochemical properties of MHC class II molecules, we have learned that the conformational heterogeneity of MHC class II induced upon binding to different peptides is a key regulator in antigen presentation and epitope selection, and a determinant of the ability of MHC class II to participate in peptide association or dissociation and interaction with the peptide editor HLA-DM.

Fig. 1

A model for heterogeneity of MHC class II conformations as the basis for DM recognition its effector function. A newly synthesized MHC class II, or DR1, molecule, occupied here by a peptide that does not fill Pocket 1, is in a ‘floppy’ or ‘open,’ DM-sensitive conformation (1). DM can interact transiently with the molecule by using the proposed ‘hit-and-run’ mechanism [39, 46] and can induce local conformational changes that lead to break in the b81His hydrogen bond between the peptide and DR1, resulting in the release of peptide (2). This generates a peptide-receptive DR1 (3), upon which several events might follow. The molecule can bind another peptide that is similar to the one described above and can then go through another round of DM-mediated dissociation (steps 1 and 2). Alternatively, in the absence of peptide, the DR1 molecule might close and become inactive over time under physiological conditions (4). The empty DR1 might now be rescued by a DM ‘hit’ to generate the peptide-receptive form again (4’). Finally, if DR1 binds a peptide that fills P1, the molecule then changes to a tight, DM-insensitive conformation (5). DM cannot interact productively with this complex, and the DR1 bound to peptide is exported to the cell surface (6)