Conformational isomers of a peptide–class II major histocompatibility complex

Abstract

The relative plasticity of peptide binding to class II major histocompatibility complex (MHC) molecules permits formation of multiple conformational isomers by the same peptide and MHC molecule; such conformers are specifically recognized by distinct subsets of T cells. Here, we review current knowledge and recent advances in our understanding of peptide-class II MHC conformational isomerism and the mechanisms that generate distinct MHC-peptide conformers. We focus on our studies of two T-cell subsets, type A and B, which recognize distinct conformers of the dominant epitope of hen egg white lysozyme presented by I-A(k). These conformers form via different pathways and in distinct intracellular vesicles: the type A conformer forms in late endosomes upon processing of native protein, while the more flexible type B conformer forms in early endosomes and at the cell surface. In this process, H2-DM acts as a conformational editor, eliminating the type B conformer in late endosomes. Type B T cells constitute a significant component of the naïve T-cell repertoire; furthermore, self-reactive type B T cells escape negative selection and are present in abundance in the periphery. Ongoing studies should elucidate the role of type B T cells in immunity to pathogens and in autoimmune pathology.

Targeting proteins to distinct subcellular compartments reveals unique requirements for MHC class I and II presentation

“…HEL is not glycosylated and is presumably taken up by macropinocytosis when offered in soluble form; HEL can bind to constituents of plasma membranes, such as phospholipids (35) and glycosaminoglycans (36), but receptor-mediated uptake has not been shown. Our data indicate that soluble HEL rapidly enters late endosomes and does not remain in early endosomes for enough time to allow processing and cross-presentation; this feature of soluble HEL trafficking also hindered MHC class II presentation of type B epitopes, which are generated exclusively in early endosomes lacking the accessory molecule DM (37).…”

The effect of pH dependence of antibody-antigen interactions on subcellular trafficking dynamics

“…Antigen loading onto MHC class II molecules can occur in both endosomal recycling compartments and late endosomes and/or lysosomes, and the site of antigen loading can affect the conformer of peptide-MHC class II complex that is displayed at the cell surface. [44][45][46][47] In addition, antibody binding to antigen has been shown in other studies to "protect" epitopes from presentation by MHC class II proteins. [48][49][50][51] Antibodies that bind with pH independence are therefore expected to have two effects on MHC class II-mediated presentation: first, they will recycle antigen away from degradative compartments through FcRnmediated bridging.…”

“…Consequently, these differences are expected to result in variations in the epitopes that are presented, at both the level of the peptide sequence and the conformer of peptide-MHC complex that is formed. 45 Although here we only consider the targeting of single epitope antigens with monoclonal antibodies, polyclonal mixes of antibodies that form multimeric immune complexes are expected to deliver antigens to late endosomes and/or lysosomes in antigen presenting cells independently of their pH dependence for antigen binding. 54,55 In summary, subcellular trafficking analyses of antigen in the presence of antibodies with a range of pH dependencies can be used to inform the dynamic behavior of targeted antigen within cells.…”

Differential Transmembrane Domain GXXXG Motif Pairing Impacts Major Histocompatibility Complex (MHC) Class II Structure

“…Identification of SDS-stable versus unstable peptide-class II complexes suggested that class II molecules could exist in at least two different conformational states, in this case driven primarily by the properties of the bound peptide (2,3). Identification of "Type A" and "Type B" T cells further suggests the existence of distinct forms of peptide-class II complexes, the formation of which is highly dependent on the mechanism of MHC class II peptide loading (4). Most recently, we identified a subset of signalingcompetent lipid raft-tropic I-A k class II molecules bearing the Ia.2 epitope, which is recognized by the 11-5.2 anti-Ia.2 mAb.…”