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A triad of molecular regions contribute to the formation of two distinct MHC class II conformers.

ABSTRACT: MHC class II molecules present antigen-derived peptides to CD4T cells to drive the adaptive immune response. Previous work has established that class II ?? dimers can adopt two distinct conformations, driven by the differential pairing of transmembrane domain GxxxG dimerization motifs. These class II conformers differ in their ability to be loaded with antigen-derived peptide and to effectively engage CD4T cells. Motif 1 (M1) paired I-A(k) class II molecules are efficiently loaded with peptides derived from the processing of B cell receptor-bound antigen, have unique B cell signaling properties and high T cell stimulation activity. The 11-5.2mAb selectively binds M1 paired I-A(k) class II molecules. However, the molecular determinants of 11-5.2 binding are currently unclear. Here, we report the ability of a human class II transmembrane domain to drive both M1 and M2 class II conformer formation. Protease sensitivity analysis further strengthens the idea that there are conformational differences between the extracellular domains of M1 and M2 paired class II. Finally, MHC class II chain alignments and site directed mutagenesis reveals a triad of molecular regions that contributes to 11-5.2mAb binding. In addition to transmembrane GxxxG motif domain pairing, 11-5.2 binding is influenced directly by ? chain residue Glu-71 and indirectly by the region around the inter-chain salt bridge formed by ? chain Arg-52 and ? chain Glu-86. These findings provide insight into the complexity of 11-5.2mAb recognition of the M1 paired I-A(k) class II conformer and further highlight the molecular heterogeneity of peptide-MHC class II complexes that drive T cell antigen recognition.

SUBMITTER: Drake LA

PROVIDER: S-EPMC4899207 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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A triad of molecular regions contribute to the formation of two distinct MHC class II conformers.

Drake Lisa A LA Drake James R JR

Molecular immunology 20160502

MHC class II molecules present antigen-derived peptides to CD4T cells to drive the adaptive immune response. Previous work has established that class II αβ dimers can adopt two distinct conformations, driven by the differential pairing of transmembrane domain GxxxG dimerization motifs. These class II conformers differ in their ability to be loaded with antigen-derived peptide and to effectively engage CD4T cells. Motif 1 (M1) paired I-A(k) class II molecules are efficiently loaded with peptides ...[more]

PMID: 27148821

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Project description:The vertebrate immune response is mediated through highly adaptive, quickly evolving cell surface receptors, the major histocompatibility complex (MHC). MHC molecules bind and present a diverse array of pathogenic molecules and trigger a cascade of defenses. Use of MHC variation as a marker for population health has also evolved quickly following advances in sequencing methods. We applied a combination of traditional and next generation sequencing methodology to characterize coding (peptide binding region) and regulatory (proximal promoter) sequence variation in MHC Class II DQA and DQB genes between estuarine and coastal populations of the bottlenose dolphin, Tursiops truncatus, an apex predator whose health status is indicative of anthropogenic impacts on the ecosystem. The coding regions had 10 alleles each at DQA and DQB; the promoters had 6 and 7 alleles at DQA and DQB, respectively with variation within key regulatory motifs. Positive selection was observed for the coding regions of both genes while both coding and promoter regions exhibited geographic differences in allele composition that likely indicates diversifying selection across habitats. Most notable was the discovery of a complete duplication of a 14-bp T-box motif in the DQA promoter. Four class II promoter regions (DQA, DQB, DRA, DRB) were characterized in species from four cetacean families (Delphinidae, Monodontidae, Lipotidae, and Physeteridae) and revealed substantial promoter structural diversity across this order. Peptide binding regions may not be the only source of adaptive potential within cetacean MHC for responding to pathogenic threats. These findings are the first analysis of cetacean MHC regulatory motifs, which may divulge unique immunogenetic strategies among cetaceans and reveal how MHC transcriptional control continues to evolve. The combined MHC regulatory and coding data provide new genetic context for distinct vulnerability profiles between coastal and estuarine populations, which are key concerns for health and risk management.

Dataset Information

A triad of molecular regions contribute to the formation of two distinct MHC class II conformers.

Publications

A triad of molecular regions contribute to the formation of two distinct MHC class II conformers.

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