Dataset Information

Restricted MHC class I A locus diversity in olive and hybrid olive/yellow baboons from the Southwest National Primate Research Center.

ABSTRACT: Baboons are valuable models for complex human diseases due to their genetic and physiologic similarities to humans. Deep sequencing methods to characterize full-length major histocompatibility complex (MHC) class I (MHC-I) alleles in different nonhuman primate populations were used to identify novel MHC-I alleles in baboons. We combined data from Illumina MiSeq sequencing and Roche/454 sequencing to characterize novel full-length MHC-I transcripts in a cohort of olive and hybrid olive/yellow baboons from the Southwest National Primate Research Center (SNPRC). We characterized 57 novel full-length alleles from 24 baboons and found limited genetic diversity at the MHC-I A locus, with significant sharing of two MHC-I A lineages between 22 out of the 24 animals characterized. These shared alleles provide the basis for development of tools such as MHC:peptide tetramers for studying cellular immune responses in this important animal model.

SUBMITTER: Morgan RA

PROVIDER: S-EPMC8130456 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Restricted MHC class I A locus diversity in olive and hybrid olive/yellow baboons from the Southwest National Primate Research Center.

Morgan Rebecca A RA Karl Julie A JA Bussan Hailey E HE Heimbruch Katelyn E KE O'Connor David H DH Dudley Dawn M DM

Immunogenetics 20180328 7

Baboons are valuable models for complex human diseases due to their genetic and physiologic similarities to humans. Deep sequencing methods to characterize full-length major histocompatibility complex (MHC) class I (MHC-I) alleles in different nonhuman primate populations were used to identify novel MHC-I alleles in baboons. We combined data from Illumina MiSeq sequencing and Roche/454 sequencing to characterize novel full-length MHC-I transcripts in a cohort of olive and hybrid olive/yellow bab ...[more]

PMID: 29594415

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Project description:Nonhuman primates are important animal models for the study of the maternal immune response to implantation within the decidua. The objective of this study was to define the placental expression of major histocompatibility complex (MHC) class I molecules in the cynomolgus (Macaca fascicularis) and vervet (African green) (Chlorocebus aethiops) monkeys. Early pregnancy (d36-42) cynomolgus and vervet placentas were obtained by fetectomy and prepared for histological evaluation. A pan-MHC class I monoclonal antibody demonstrated MHC class I expression in both vervet and cynomolgus placental trophoblasts, with particularly high expression in the villous syncytium, as previously shown in the rhesus and baboon. Placental cytotrophoblasts were isolated by enzymatic dispersion and gradient centrifugation and cultured, and multicolor flow cytometry was used to phenotype cell populations. Culture of isolated villous cytotrophoblasts demonstrated that MHC class I expression was linked to syncytiotrophoblast differentiation. A monoclonal antibody against Mamu-AG, the nonclassical MHC class I homolog of HLA-G in the rhesus monkey, demonstrated intense immunostaining and cell surface expression in cynomolgus placental trophoblasts; however, staining with vervet placenta and cells was low and inconsistent. Reverse transcriptase polymerase chain reaction was used to clone MHC class I molecules expressed in cynomolgus and vervet placentas. While Mafa-AG messenger RNA (mRNA) was readily detectable in cynomolgus placental RNA and was >99% identical at the amino acid level with Mamu-AG, 7/8 Chae-AG complementary DNAs had an unusual 16 amino acid repeat in the alpha1 domain, and all clones had an unexpected absence of the early stop codon at the 3'-end of the mRNA diagnostic for rhesus, cynomolgus, and baboon AG mRNAs, as well as HLA-G. We conclude that while the vervet monkey has retained the placental expression of a primate-specific nonclassical MHC class I locus, diversity is also revealed in this locus expressed at the maternal-fetal interface, thought to participate in placental regulation of the maternal immune response to embryo implantation and pregnancy.

Project description:Epitopes that arise from a somatic mutation, also called neoepitopes, are now known to play a key role in cancer immunology and immunotherapy. Recent advances in high-throughput sequencing have made it possible to identify all mutations and thereby all potential neoepitope candidates in an individual cancer. However, most of these neoepitope candidates are not recognized by T cells of cancer patients when tested in vivo or in vitro, meaning they are not immunogenic. Especially in patients with a high mutational load, usually hundreds of potential neoepitopes are detected, highlighting the need to further narrow down this candidate list. In our study, we assembled a dataset of known, naturally processed, immunogenic neoepitopes to dissect the properties that make these neoepitopes immunogenic. The tools to use and thresholds to apply for prioritizing neoepitopes have so far been largely based on experience with epitope identification in other settings such as infectious disease and allergy. Here, we performed a detailed analysis on our dataset of curated immunogenic neoepitopes to establish the appropriate tools and thresholds in the cancer setting. To this end, we evaluated different predictors for parameters that play a role in a neoepitope's immunogenicity and suggest that using binding predictions and length-rescaling yields the best performance in discriminating immunogenic neoepitopes from a background set of mutated peptides. We furthermore show that almost all neoepitopes had strong predicted binding affinities (as expected), but more surprisingly, the corresponding non-mutated peptides had nearly as high affinities. Our results provide a rational basis for parameters in neoepitope filtering approaches that are being commonly used. Abbreviations: SNV: single nucleotide variant; nsSNV: nonsynonymous single nucleotide variant; ROC: receiver operating characteristic; AUC: area under ROC curve; HLA: human leukocyte antigen; MHC: major histocompatibility complex; PD-1: Programmed cell death protein 1; PD-L1 or CTLA-4: cytotoxic T-lymphocyte associated protein 4.

Dataset Information

Restricted MHC class I A locus diversity in olive and hybrid olive/yellow baboons from the Southwest National Primate Research Center.

Publications

Restricted MHC class I A locus diversity in olive and hybrid olive/yellow baboons from the Southwest National Primate Research Center.

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