HLA-B polymorphisms and intracellular assembly modes

doi:10.1016/j.molimm.2015.07.007

Molecular Immunology

Volume 68, Issue 2, Part A, December 2015, Pages 89-93

https://doi.org/10.1016/j.molimm.2015.07.007 Get rights and content

Highlights

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Peptide-deficient forms of HLA-B molecules have varying stabilities.
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HLA-B molecules can assemble via tapasin-dependent or tapasin-independent routes.
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Assembly modes may confer selective immune advantages for CTL or NK recognition.

Abstract

Human leukocyte antigen (HLA) class I molecules are ligands for antigen receptors of cytotoxic T cells (CTL) and inhibitory receptors of natural killer (NK) cells. The high degree of HLA class I polymorphism allows for the selection of distinct and diverse sets of antigenic peptide ligands for presentation to CTL. The extensive polymorphisms of the HLA class I genes also result in large variations in their intracellular folding and assembly characteristics. Recent findings indicate that North American HLA-B variants differ significantly in the stabilities of their peptide-deficient forms and in the requirements for the endoplasmic reticulum (ER)-resident factor tapasin for proper assembly. In HIV-infected individuals, the presence of tapasin-independent HLA-B allotypes links to more rapid progression to death. Further studies are important to better understand how the intrinsic structural characteristics of HLA class I folding intermediates affect immune responses mediated by CTL and NK cells.

Section snippets

MHC class I molecules as ligands for cytotoxic T cell (CTL) and natural killer (NK) cell receptors

Major histocompatibility complex (MHC) class I molecules are ligands for antigen receptors of CD8⁺ CTL (Bjorkman, 1997, Rossjohn et al., 2014) and for inhibitory receptors of natural killer (NK) cells (Parham and Moffett, 2013). In a normal healthy cell, MHC class I heavy chains and light chains (β2-microglobulin; β2m) form heterodimers that bind short peptides derived from self-proteins. In cells infected with an intracellular pathogen or in cancer cells, a subset of the cellular peptides

MHC class I assembly in the ER

The assembly of MHC class I molecules occurs within the ER of cells, and involves the assembly factors TAP (transporter associated with antigen presentation) (Mayerhofer and Tampe, 2015) and tapasin (Blum et al., 2013), that are also encoded within the MHC gene complex, that includes the MHC class I heavy chain genes. In the endogenous pathway of antigen presentation, peptides that derive from cytosolic proteolysis are transported into the ER by TAP. TAP is comprised of two subunits, TAP1 and

MHC polymorphisms and assembly variations

Human TAP and tapasin sequences have no known functional polymorphisms. Rat TAP2 and chicken TAP1 and TAP2 sequences have functional polymorphisms that are known to affect peptide transport specificity. Chicken MHC haplotypes have TAP1, TAP2 and tapasin allele variants that are optimally configured for the transport and binding of peptide sequences relevant to the encoded MHC class I (Kaufman, 2015). Further studies of such functional polymorphisms are expected to provide insights into peptide

HLA-B polymorphisms and AIDS outcomes

The extreme polymorphism of the MHC class I molecules reflects evolutionary adaptations of T and NK cell responses to pathogens, in addition to NK cell functions during reproduction (Parham and Moffett, 2013). Since different combinations of HLA-A, B and C variants are present within individuals in a population, distinct sets of pathogen-derived peptides are presented during infections, resulting in the induction of CTL responses with distinct specificities. Thus, it might be expected that HLA

Acknowledgements

This work was funded by a NIH grant AI044115 (to MR). This work was supported in part by the University of Michigan Medical School Fast Forward Protein Folding Diseases Initiative.

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In this study, we illustrated the interaction mechanism by studying how TCE affects the binding affinity of peptides to HLA-B molecules. HLA-B is part of the adaptive immune system and the function of HLA-B is to present a vast array of antigenic peptides to T cells, which subsequently initiate different immunological reactions [27,28]. We identified the motif characteristics of HLA-B*13:01 and HLA-B*13:02-binding peptides, which have excellent consistency with large peptidome datasets [29].
Recently, Trichloroethylene (TCE) induced TCE hypersensitivity syndrome (THS) has attracted the attention of many researchers in the field of environmental and occupational health. Studies have revealed that Human leukocyte antigen (HLA) polymorphisms were the important genetic determinants of the diseases, but the potential molecular mechanism remains unclear.
This study aimed to investigate the association between THS and HLA at the molecular level.
We chose the human B-lymphoblastoid cell line Hmy2.C1R transfected with cDNA of HLA-B*13:01 and HLA-B*13:02 to analyze the characteristics of HLA-B-binding peptides and investigate the effect of TCE on the binding affinity of peptides to the HLA-B molecules. Further, the mathematical model was used to identify the possible interaction between TCE and HLA-B*13:01 or HLA-B*13:02 molecule.
54 HLA-B*13:01-binding peptides and 85 HLA-B*13:02-binding peptides were identified. Comparing the protein sequences of HLA-B*13:01 and HLA-B*13:02, amino acids were different at positions 94, 95 and 97. The results of the binding affinity of self-peptides to HLA molecules in the presence of TCE showed that TCE significantly decreased the binding affinity of peptides to HLA-B*13:01 only, but did not affect that of HLA-B*13:02. Molecular docking model showed that there was a unique high-affinity binding mode between TCE and HLA-B*13:01 (but not HLA-B*13:02), and the binding site located in the region of F pocket, suggesting that the unique structure of the F pocket of HLA-B*13:01 might provide the possibility of binding TCE. The pathogenesis of interaction between HLA-B*13:01 and TCE might belong to the model of the alteration of the HLA-presented self-peptide repertoire.
This study explored the molecular mechanism of the association between THS and HLA-B*13:01, and had important implications for understanding the role of gene-environment interaction in the development of complex environment-related diseases.
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A comparison shows that the rank order of peptide repertoire determined by predictions of Dengue peptides (Paul et al., 2013) does not correlate with peptide motifs of many class I molecules, as illustrated by the A1, A24 and B7 supertypes (Kaufman, 2020), so that these two properties may be disentangled experimentally (Fig. 3). Other important papers (Rizvi et al., 2014, Raghavan and Geng, 2015) focused on the relative tapasin-dependence of human class I alleles compared to their role in controlling HIV progression. The initial studies used transfection of 50 HLA-B alleles into tapasin-deficient and wild-type cells, finding a hierarchy based on tapasin-dependence for cell surface expression.
Chickens have played many roles in human societies over thousands of years, most recently as an important model species for scientific discovery, particularly for embryology, virology and immunology. In the last few decades, biomedical models like mice have become the most important model organism for understanding the mechanisms of disease, but for the study of outbred populations, they have many limitations. Research on humans directly addresses many questions about disease, but frank experiments into mechanisms are limited by practicality and ethics. For research into all levels of disease simultaneously, chickens combine many of the advantages of humans and of mice, and could provide an independent, integrated and overarching system to validate and/or challenge the dogmas that have arisen from current biomedical research. Moreover, some important systems are simpler in chickens than in typical mammals. An example is the major histocompatibility complex (MHC) that encodes the classical MHC molecules, which play crucial roles in the innate and adaptive immune systems. Compared to the large and complex MHCs of typical mammals, the chicken MHC is compact and simple, with single dominantly-expressed MHC molecules that can determine the response to infectious pathogens. As a result, some fundamental principles have been easier to discover in chickens, with the importance of generalist and specialist MHC alleles being the latest example.
Strategies for the measurements of expression levels and half-lives of HLA class I allotypes
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Peptides that bind HLA class I molecules typically derive from the cytosol, are transported into the endoplasmic reticulum (ER) via the transporter associated with antigen processing (TAP). In the ER, peptides assemble with HLA class I heterodimers with the assistance of tapasin and the chaperone/oxidoreductase complex, calreticulin and ERp57 (reviewed in [22,23]). HLA-B allotypes are known to display varying stabilities and dependencies on assembly factors tapasin and TAP [24–28].
HLA class I molecules are highly polymorphic cell surface proteins that trigger immune responses by CD8⁺ T cells and natural killer (NK) cells. Most humans express six different HLA class I proteins encoded by the HLA-A, HLA-B and HLA-C genes. HLA class I molecules bind to peptide antigens and present these antigens to T cell receptors (TCR) of CD8⁺ T cells. HLA class I expression levels also regulate NK cell activation. The presence of individual HLA class I genes is linked to many different disease, transplantation and therapy outcomes. An understanding of HLA class I expression and stability patterns is fundamentally important towards a better understanding of the associations of HLA class I genes with disease and treatment outcomes, and towards HLA class I targeting for vaccine development. Quantitative flow cytometry allows for assessments of variations in expression levels of HLA class I molecules in cells from a single blood donor over time, as well as averaged measurements across donors for the same allotype. Since all HLA class I molecules are structurally-related, cellular measurements of the HLA class I expression levels and stabilities of individual variants in human cells require careful choices of donors and antibodies, which are discussed here.
Molecular and pathogenic effects of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in MHC-I-associated inflammatory disorders: Towards a unifying view
2016, Molecular Immunology
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The binding of large peptide repertoires is an essential requisite for MHC-I folding and export (Ljunggren et al., 1990). The availability of suitable peptides in the ER will influence folding in an allotype-dependent way (Hill et al., 1993; Rizvi et al., 2014; Raghavan and Geng, 2015). The strength of peptide binding determines MHC-I stability, the half-life of the MHC-I/peptide complexes and their dissociation at the cell surface.
The inflammatory diseases that are most strongly associated with major histocompatibility Complex class I (MHC-I) alleles are also influenced by endoplasmic reticulum aminopeptidase (ERAP) 1 and/or 2, often in epistasis with the susceptibility MHC-I allele. This review will focus on the four major MHC-I-associated inflammatory disorders: ankylosing spondylitis, birdshot chorioretinopathy, Behçet’s disease and psoriasis. The genetics of ERAP1/ERAP2 association and the alterations induced by polymorphism of these enzymes on the risk MHC-I allotypes will be examined. A pattern emerges of analogous effects on peptide length, sequence and affinity of disparate peptidomes, suggesting that similar peptide-mediated mechanisms underlie the pathogenesis and the joint contribution of ERAP1/ERAP2 and MHC-I to distinct inflammatory diseases. Processing of specific antigens, peptide-dependent changes in global properties of the MHC-I molecules, such as folding and stability, or both may be pathogenic.
A SYSTEMATIC REVIEW ON THE INFLUENCE OF HLA-B POLYMORPHISMS ON HIV-1 MOTHER-TO-CHILD-TRANSMISSION
2019, Brazilian Journal of Infectious Diseases
Citation Excerpt :
Currently, there is great interest on variants of HLA genes codifying regions that can affect the host immune response to HIV infection. HLA alleles are responsible for antigen presentation to CD4+ and CD8+ T cells.5–9 Despite strong evidence on the important role of HLA-B polymorphisms on HIV-1 MTCT risk, the available data are often contradictory.10–12
Mother-to-child-transmission (MTCT) is the main route of HIV-1 infection in children. Genetic studies suggest HLA-B alleles play an important role on HIV-1 transmission, progression, and control of HIV-1 infection.
To evaluate which polymorphisms of HLA-B are involved in HIV-1 MTCT.
Two independent reviewers performed a systematic review on search engines PubMed, Europe PMC, Cochrane, Scientific Electronic Library Online (SciELO), and Literatura Latino-americana e do Caribe em Ciências da Saúde (Lilacs), using the following key terms: “HIV infection”, “HIV newborn”, “HLA polymorphisms”, “HLA-B”, and “Mother to child transmission”. All studies focusing on evaluation of HIV-1 MTCT, HIV infection evolution, and molecular analyses of HLA-B in children were selected.
Nine studies fulfilled the inclusion criteria. Sixteen HLA-B alleles groups were associated with HIV-1 infection; seven of them (43.8%) were related to slow disease progression or reduced risk of MTCT, while six (37.5%) alleles groups were linked to a faster progression of HIV infection in children and to increased risk of MTCT. The available evidence suggest that HLA-B*57 group allele is associated with slow disease progression, while HLA-B*35 group allele is associated to increased risk of MTCT and rapid disease progression in infected children. The role of HLA-B*18, B*58 and B*44 are still controversial because they were associated to both, protection against MTCT, and to higher HIV replicative capacity, in different studies.
HLA-B*57 group allele can be protective against MTCT while HLA-B*35 groups alleles are consistently associated with HIV-1 MTCT.
Assessing HLA imputation accuracy in a West African population
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HLA-B polymorphisms and intracellular assembly modes

Highlights

Abstract

Section snippets

MHC class I molecules as ligands for cytotoxic T cell (CTL) and natural killer (NK) cell receptors

MHC class I assembly in the ER

MHC polymorphisms and assembly variations

HLA-B polymorphisms and AIDS outcomes

Acknowledgements

Cell

J. Biol. Chem.

Curr. Opin. Immunol.

Front. Immunol.

J. Mol. Biol.

Mol. Immunol.

Immunity

Trends Immunol.