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141 results for “MHC class I”
Tumor MHC Class I Expression Associates with Interleukin-2 Response in Melanoma
<p>The processed multiplexed IF data and sample ID corresponding to the raw data in record (https://zenodo.org/record/4300912#.Y-WGBuzMKY-). All code used to produce the results of this study are available at <a href="https://github.com/cBio-MSKCC/Halo_Melanoma_IL2">https://github.com/cBio-MSKCC/Halo_Melanoma_IL2</a>.</p>
Relationship between genome-wide and MHC class I and II genetic diversity and complementarity in a nonhuman primate
<p>Although mate choice is expected to favor partners with advantageous genetic properties, the relative importance of genome-wide characteristics, such as overall heterozygosity or kinship, versus specific loci, is unknown. To disentangle genome-wide and locus-specific targets of mate choice, we must first understand congruence in global and local variation within the same individual. This study compares genetic diversity, both absolute and relative to other individuals (e.g., complementarity), assessed across the genome to that found at the major histocompatibility complex (MHC), a hyper-variable gene family integral to immune system function and implicated in mate choice across species. Using DNA from 22 captive olive baboons (<em>Papio anubis</em>), we conducted double digest restriction-site associated DNA sequencing to estimate genome-wide heterozygosity and kinship and sequenced two class I and two class II MHC loci. We found that genome-wide diversity was not associated with MHC diversity, and that diversity at class I MHC loci was not correlated with diversity at class II loci. Additionally, kinship was a significant predictor of the number of MHC alleles shared between dyads at class II loci. Our results provide further evidence of the strong selective pressures maintaining genetic diversity at the MHC in comparison to other randomly selected sites throughout the genome. Furthermore, our results indicate that class II MHC disassortative mate choice may mediate inbreeding avoidance in this population. Our study suggests that mate choice favoring genome-wide genetic diversity is not always synonymous with mate choice favoring MHC diversity, and highlights the importance of controlling for kinship when investigating MHC-associated mate choice.</p>
Individual allotype responses to HEK-293T-based cell lines ex-pressing single MHC class I chain-related gene B alleles
<p><span>Figure S1.</span><span> Individual allotype responses between 64 sera collected from kidney transplant patients and 5 single </span><span>MICB</span><span> allele-expressing cell lines established in </span><span>HLA</span><span> class I, </span><span>MICA,</span><span> and </span><span>MICB</span><span>-null HEK-293T cells. </span><span>HLA</span><span> class I, </span><span>MICA,</span><span> and </span><span>MICB</span><span> genes were removed using CRISPR/Cas9 in previous studies [20, 21]. Some of the 64 sera showed responses to single </span><span>MICA</span><span> allele-expressing cell lines [21]. However, none of the 64 sera showed individual allotype responses in this study.</span></p>
Meta-analysis of major histocompatibility complex (MHC) class IIA reveals polymorphism and positive selection in many vertebrate species
<p>Pathogen-mediated selection and sexual selection are important drivers of evolution. Both processes are known to target genes of the major histocompatibility complex (MHC), a gene family encoding cell-surface proteins that display pathogen peptides to the immune system. The MHC is also a model for understanding processes such as gene duplication and trans-species allele sharing. The class II MHC protein is a heterodimer whose peptide-binding groove is encoded by an MHC-IIA gene and an MHC-IIB gene. However, our literature review found that class II MHC papers on infectious disease or sexual selection included IIA data only 18% and 9% of the time, respectively. To assess whether greater emphasis on MHC-IIA is warranted, we analyzed MHC-IIA sequence data from 50 species of vertebrates (fish, amphibians, birds, mammals) to test for polymorphism and positive selection. We found that the number of MHC-IIA alleles within a species was often high, and covaried with sample size and number of MHC-IIA genes assayed. While MHC-IIA variability tended to be lower than that of MHC-IIB, the difference was only ~25%, with ~3 fewer IIA alleles than IIB. Furthermore, the unexpectedly high MHC-IIA variability showed clear signatures of positive selection in most species, and positive selection on MHC-IIA was stronger in fish than in other surveyed vertebrate groups. Our findings underscore that MHC-IIA can be an important target of selection. Future work should therefore expand the characterization of MHC-IIA at both allelic and genomic scales, and incorporate MHC-IIA into models of fitness consequences of MHC variation.</p>
MHC class II genes mediate susceptibility and resistance to coronavirus infections in bats
<p>Understanding the immunogenetic basis of coronavirus (CoV) susceptibility in major pathogen reservoirs, such as bats, is central to infer their zoonotic potential. Members of the cryptic <em>Hipposideros</em> bat species complex differ in CoV susceptibility, but the underlying mechanisms remain unclear. The genes of the major histocompatibility complex (MHC) are the best understood genetic basis of pathogen resistance, and differences in MHC diversity are one possible reason for asymmetrical infection patterns among closely related species. Here, we aimed to link asymmetries in observed CoV (CoV-229E, CoV-2B, and CoV-2Bbasal) susceptibility to immunogenetic differences amongst four <em>Hipposideros</em> bat species. From the 2,072 bats assigned to their respective species using the mtDNA cytochrome b gene, members of the most numerous and ubiquitous species, <em>Hipposideros caffer</em> D, were most infected with CoV-229E and SARS-related CoV-2B. Using a subset of 569 bats we determined that much of the existent allelic and functional (i.e., supertype) MHC DRB class II diversity originated from common ancestry. One MHC supertype shared amongst all species, ST12, was consistently linked to susceptibility with CoV-229E, which is closely related to the common cold agent HCoV-229E, and infected bats with ST12 had a lower body condition. The same MHC supertype was connected to resistance to CoV-2B, and bats with ST12 were less likely be co-infected with CoV-229E and CoV-2B. Our work suggests a role of immunogenetics in determining CoV susceptibility in bats. We advocate for the preservation of functional genetic and species diversity in reservoirs as means of mitigating the risk of disease spillover.</p>
Meta-analysis of major histocompatibility complex (MHC) class IIA reveals polymorphism and positive selection in many vertebrate species
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MHC class II genes mediate susceptibility and resistance to coronavirus infections in bats
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Relationship between genome-wide and MHC class I and II genetic diversity and complementarity in a nonhuman primate
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Sequence-structure-function relationships in class I MHC: a local frustration perspective
<p>Class I Major Histocompatibility Complex (MHC) binds short antigenic peptides with the help of Peptide Loading Complex (PLC), and presents them to T-cell Receptors (TCRs) of cytotoxic T-cells and Killer-cell Immunglobulin-like Receptors (KIRs) of Natural Killer (NK) cells. With more than 10000 alleles, the Human Leukocyte Antigen (HLA) chain of MHC is the most polymorphic protein in humans. This allelic diversity provides a wide coverage of peptide sequence space, yet does not affect the three-dimensional structure of the complex. Moreover, TCRs mostly interact with pMHC in a common diagonal binding mode, and KIR-pMHC interaction is allele-dependent. With the aim of establishing a framework for understanding the relationships between polymorphism (sequence), structure (conserved fold) and function (protein interactions) of the MHC, we performed here a local frustration analysis on pMHC homology models covering 1436 HLA I alleles. An analysis of local frustration profiles indicated that (1) variations in MHC fold are unlikely due to minimally-frustrated and relatively conserved residues within the HLA peptide-binding groove, (2) high frustration patches on HLA helices are either involved in or near interaction sites of MHC with the TCR, KIR, or Tapasin of the PLC, and (3) peptide ligands mainly stabilize the F-pocket of HLA binding groove.</p>
MHC class II genotype-by-pathogen genotype interaction for infection prevalence in a natural rodent-Borrelia system
<p><span>MHC genes are extraordinarily polymorphic in most taxa. Host-pathogen coevolution driven by negative frequency-dependent selection (NFDS) is one of the main hypotheses for the maintenance of such immunogenetic variation. Here we test a critical but rarely tested assumption of this hypothesis—that MHC alleles affect resistance/susceptibility to a pathogen in a strain-specific way, i.e. that there is a host genotype-by-pathogen genotype interaction. </span><span>In a field study of bank voles naturally infected with the tick-transmitted bacterium </span><em><span>Borrelia afzelii</span></em><span>, we tested for MHC class II (</span><em><span>DQB</span></em><span>) genotype-by-</span><span><em>B. afzelii</em> </span><span>strain interactions for infection prevalence between ten </span><em><span>DQB</span></em><span><em> </em>alleles and seven strains. One allele (<em>DQB</em>*37) showed an interaction</span><span>, </span><span>such that voles carrying <em>DQB</em>*37 had higher prevalence of two strains and lower prevalence of one strain than individuals without the allele. These findings were corroborated by analyses of strain composition of infections, which revealed an effect of <em>DQB</em>*37 in the form of lower </span><span>b</span><span> diversity among infections in voles carrying the allele. Taken together, these results provide rare support at the molecular genetic level for a key assumption of models of antagonistic coevolution through NFDS. </span></p>
Trans-specific polymorphism and the convergent evolution of supertypes in MHC class II genes in Darters (Etheostoma)
<p>Major Histocompatibility Complex (MHC) genes are one of the most polymorphic gene groups known in vertebrates. MHC genes also exhibit allelic variants that are shared among taxa, referred to as trans-specific polymorphism (TSP). The role that selection plays in maintaining such high diversity within species, as well as TSP, is an ongoing discussion in biology. In this study we used deep-sequencing techniques to characterize MHC class IIb gene diversity in three sympatric species of darters. We found at least 5 copies of the MHC gene in darters, with 126 genetic variants encoding 122 unique amino acid sequences. We identified four supertypes based on the binding properties of proteins encoded by the sequences. Although each species had a unique pool of variants, many variants were shared between species pairs and across all three species. Phylogenetic analysis showed that the variants did not group together monophyletically based on species identity or on supertype. An expanded phylogenetic analysis showed that some darter alleles grouped together with alleles from other percid fishes. Our findings show that TSP occurs in darters, which suggests that balancing selection is acting at the genotype level. Supertypes, however, are most likely evolving convergently, as evidenced by the fact that alleles do not form monophyletic groups based on supertype. Our research demonstrates that selection may be acting differently on MHC genes at the genotype and supertype levels, selecting for the maintenance of high genotypic diversity while driving the convergent evolution of similar MHC phenotypes across different species.</p>
Data from: Investigating the human and non-obese diabetic mouse MHC class II immunopeptidome using protein language modelling.
<p><strong>Background</strong>: Identifying peptides associated with the major histocompability complex class II (MHCII) is a central task in the evaluation of the immunoregulatory function of therapeutics and drug prototypes. MHCII-peptide presentation prediction has multiple biopharmaceutical applications, including the safety assessment of biologics and engineered derivatives in silico, or the fast progression of antigen-specific immunomodulatory drug discovery programs in immune disease and cancer. This has resulted in the collection of large–scale data sets on adaptive immune receptor antigenic responses and MHC-associated peptide proteomics. In parallel, recent deep learning algorithmic advances in natural language processing (NLP) and protein language modelling (PLM) have shown potential in leveraging large collections of sequence data and improve MHC presentation prediction. <strong>Methodology</strong>: We trained a compact transformer model (AEGIS) on human and mouse MHCII immunopeptidome data, including a preclinical murine model, and evaluated its performance on the peptide presentation prediction task. <strong>Data</strong>: The data and models used in AEGIS are contained in the uploaded tar files. <strong>Results</strong>: The transformer performs on par with existing deep learning algorithms and that combining datasets from multiple organisms increases model performance (see preprint). We trained variants of the model with and without MHCII information. In both alternatives, the inclusion of peptides presented by the I-Ag7 MHC class II molecule expressed by the non-obese diabetic (NOD) mice enabled the in silico prediction of presented peptides in a preclinical type 1 diabetes model organism, which has promising therapeutic applications.</p>
Effect of Methyldopa on MHC Class II Antigen Presentation in Type 1 Diabetes
ClinicalTrials.gov study NCT01883804. IPD Sharing: Not stated. Countries: 1. Publications: 2.
Data from: MHC class II supertypes affect survival and lifetime reproductive success in a migratory songbird
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MHC class II genotype-by-pathogen genotype interaction for infection prevalence in a natural rodent-Borrelia system
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Sequence-structure-function relationships in class I MHC: a local frustration perspective
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Trans-specific polymorphism and the convergent evolution of supertypes in MHC class II genes in Darters (Etheostoma)
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Data from: Extra-pair mating in a passerine bird with highly duplicated MHC class II: Preference for the golden mean
Genes of the major histocompatibility complex (MHC) are essential in vertebrate adaptive immunity, and they are highly diverse and duplicated in many lineages. While it is widely established that pathogen-mediated selection maintains MHC diversity through balancing selection, the role of mate choice in shaping MHC diversity is debated. Here, we investigate female mating preferences for MHC class II (MHCII) in the bluethroat (<i></i>Luscinia svecica<i></i>), a passerine bird with high levels of extra-pair paternity and extremely duplicated MHCII. We genotyped family samples with mixed paternity and categorized their MHCII alleles according to their functional properties in peptide binding. Our results strongly indicate that females select extra-pair males in a non-random, self-matching manner that provides offspring with an allelic repertoire size closer to the population mean, as compared to offspring sired by the social male. This is consistent with a "compatible genes" model for extra-pair mate choice where the optimal allelic diversity is intermediate, not maximal. This "golden mean" presumably reflects a trade-off between maximizing pathogen recognition benefits and minimizing autoimmunity costs. Our study exemplifies how mate choice can reduce the population variance in individual MHC diversity and exert strong stabilizing selection on the trait. It also supports the hypothesis that extra-pair mating is adaptive through enhanced genetic quality of offspring.
Data from: MHC class I expression dependent on bacterial infection and parental factors in whitefish embryos (Salmonidae)
Ecological conditions can influence not only the expression of a phenotype, but also the heritability of a trait. As such, heritable variation for a trait needs to be studied across environments. We have investigated how pathogen challenge affects the expression of MHC genes in embryos of the lake whitefish Coregonus palaea. In order to experimentally separate paternal (i.e. genetic) from maternal and environmental effects, and determine whether and how stress affects the heritable variation for MHC expression, embryos were produced in full-factorial in vitro fertilizations, reared singly, and exposed at 208 degree days (late-eyed stage) to either one of two strains of Pseudomonas fluorescens that differ in their virulence characteristics (one increased mortality, while both delayed hatching time). Gene expression was assessed 48 h postinoculation, and virulence effects of the bacterial infection were monitored until hatching. We found no evidence of MHC class II expression at this stage of development. MHC class I expression was markedly down-regulated in reaction to both pseudomonads. While MHC expression could not be linked to embryo survival, the less the gene was expressed, the earlier the embryos hatched within each treatment group, possibly due to trade-offs between immune function and developmental rate or further factors that affect both hatching timing and MHC expression. We found significant additive genetic variance for MHC class I expression in some treatments. That is, changes in pathogen pressures could induce rapid evolution in MHC class I expression. However, we found no additive genetic variance in reaction norms in our study population.
Data from: TAPBPR mediates peptide dissociation from MHC class I using a leucine lever
Tapasin and TAPBPR are known to perform peptide editing on major histocompatibility complex class I (MHC I) molecules, however, the precise molecular mechanism(s) involved in this process remain largely enigmatic. Here, using immunopeptidomics in combination with novel cell-based assays that assess TAPBPR-mediate peptide exchange, we reveal a critical role for the K22-D35 loop of TAPBPR in mediating peptide exchange on MHC I. We identify a specific leucine within this loop that enables TAPBPR to facilitate peptide dissociation from MHC I. Moreover, we delineate the molecular features of the MHC I F pocket required for TAPBPR to promote peptide dissociation in a loop-dependent manner. These data reveal that chaperone-mediated peptide editing of MHC I can occur by different mechanisms dependent on the C-terminal residue that the MHC I accommodates in its F pocket and provide novel insights that may inform the therapeutic potential of TAPBPR manipulation to increase tumour immunogenicity.
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