Archaic humans have contributed to large-scale variation in modern human T cell receptor genes

Corcoran, Martin; Chernyshev, Mark; Mandolesi, Marco; Narang, Sanjana; Kaduk, Mateusz; Ye, Kewei; Sundling, Christopher; Färnert, Anna; Kreslavsky, Taras; Bernhardsson, Carolina; Larena, Maximilian; Jakobsson, Mattias; Hedestam, Gunilla B. Karlsson

doi:10.1016/j.immuni.2023.01.026

Cited by 15 publications

(5 citation statements)

References 80 publications

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“…The indicated number of functional gene segments, based on data from the International Immunogenetics Information System (IMGT, https://www.imgt.org/IMGTrepertoire/ ), does not include pseudogenes and open-reading frames (ORFs). Recently published data indicate that inter-individual allelic variation in TCR genes may further broaden the TCR diversity reported here ( 4 ).…”

mentioning

confidence: 63%

Editorial: T cell specificity and cross-reactivity – implications in physiology and pathology

Latorre,

Monticelli,

Wypych

et al. 2024

Front. Immunol.

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confidence: 63%

Editorial: T cell specificity and cross-reactivity – implications in physiology and pathology

Latorre,

Monticelli,

Wypych

et al. 2024

Front. Immunol.

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“…Nonetheless, the only clearly established biochemical properties of BTNL3+8 heteromers, and of their mouse counterparts, is to engage intestinal γδ TCR Vγ chains. Interestingly, direct evidence germane to the importance of CD103 + Vγ4 + cell regulation may in the near future be provided by analyses of IBD incidence and progression in individuals carrying recently described TRGV4 alleles encoding chains that show reduced responsiveness to BTNL3+BTNL8 ( 60 ).…”

Section: Discussionmentioning

confidence: 99%

Conserved γδ T cell selection by BTNL proteins limits progression of human inflammatory bowel disease

Dart,

Zlatareva,

Vantourout

et al. 2023

Science

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Murine intraepithelial γδ T cells include distinct tissue-protective cells selected by epithelial butyrophilin-like (BTNL) heteromers. To determine whether this biology is conserved in humans, we characterized the colonic γδ T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset coexpressing T cell receptor Vγ4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease, whereas on-treatment CD103 + γδ T cell restoration was associated with sustained inflammatory bowel disease remission. Moreover, CD103 + Vγ4 + cell dysregulation and loss were also displayed by humans with germline BTNL3/BTNL8 hypomorphism, which we identified as a risk factor for penetrating Crohn’s disease (CD). Thus, BTNL-dependent selection and/or maintenance of distinct tissue-intrinsic γδ T cells appears to be an evolutionarily conserved axis limiting the progression of a complex, multifactorial, tissue-damaging disease of increasing global incidence.

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“…Most immune repertoire research has focused primarily on somatically derived immune receptor diversity, namely V(D)J recombination and somatic hypermutation (SHM) diversity. In recent years, however, the extent of population diversity has begun to be appreciated at both the immunoglobulin (IG) (Gidoni et al, 2019; Mikocziova et al 2021; Corcoran et al 2023; Rodriguez et al 2023; Gibson et al 2022) and T cell receptor (TR) loci (Omer et al, 2022; M. Corcoran et al, 2023; Rodriguez et al 2022). The functional significance of allelic variation in adaptive immune loci has also been recognized in the context of influenza, HIV and COVID-19 immunity and vaccination (Avnir et al 2016; Lee et al 2021; Leggat et al 2022; Pushparaj et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…However, structural variation is quite common (Rodriguez et al 2023) in the IG and TR loci, while most new IG and TR sequence data is coming from Rep-Seq experiments, and can be hard to map to a particular gemline locus position. Other databases of immune receptor gene alleles have been introduced, such as pmTR (Dekker, van Dongen, Reinders, & Khatri, 2022, https://pmtrig.lumc.nl/), IgPdb (https://cgi.cse.unsw.edu.au/∼ihmmune/IgPdb) and Karolinska Institutet human T-cell receptor database (M. Corcoran et al, 2023, https://gkhlab.gitlab.io/tcr/). A comprehensive and well-maintained database of immune receptor gene alleles, including allelic variants inferred from Rep-Seq, is VDJbase (Omer et al 2020, https://vdjbase.org/).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ultrasensitive allele inference from immune repertoire sequencing data with MiXCR

Mikelov,

Nefediev,

Tashkeev

et al. 2023

Preprint

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Allelic variability in the adaptive immune receptor loci, which harbor the gene segments that encode B cell and T cell receptors (BCR/TCR), has been shown to be of critical importance for immune responses to pathogens and vaccines. In recent years, B cell and T cell receptor repertoire sequencing (Rep-Seq) has become widespread in immunology research making it the most readily available source of information about allelic diversity in immunoglobulin (IG) and T cell receptor (TR) loci in different populations. Here we present a novel algorithm for extra-sensitive and specific variable (V) and joining (J) gene allele inference and genotyping allowing reconstruction of individual high-quality gene segment libraries. The approach can be applied for inferring allelic variants from peripheral blood lymphocyte BCR and TCR repertoire sequencing data, including hypermutated isotype-switched BCR sequences, thus allowing high-throughput genotyping and novel allele discovery from a wide variety of existing datasets. The developed algorithm is a part of the MiXCR platform (https://mixcr.com) and can be incorporated into any pipeline utilizing upstream processing with MiXCR. We demonstrate the accuracy of this approach using Rep-Seq paired with long-read genomic sequencing data, comparing it to a widely used algorithm, TIgGER. We applied the algorithm to a large set of heavy chain Rep-Seq data from 428 donors of ancestrally diverse population groups, and to the largest reported full-length TCR alpha and beta chain Rep-Seq dataset, representing 134 individuals. This allowed us to assess the genetic diversity of genes within the immunoglobulin heavy chain (IGH) and TCR alpha and beta loci (TRA; TRB) in different populations and demonstrate the connection between antibody repertoire gene usage and the number of allelic variants present in the population. Finally we established a database of allelic variants of V and J genes inferred from Rep-Seq data and their population frequencies with free public access at https://vdj.online.

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Archaic humans have contributed to large-scale variation in modern human T cell receptor genes

Cited by 15 publications

References 80 publications

Editorial: T cell specificity and cross-reactivity – implications in physiology and pathology

Editorial: T cell specificity and cross-reactivity – implications in physiology and pathology

Conserved γδ T cell selection by BTNL proteins limits progression of human inflammatory bowel disease

Ultrasensitive allele inference from immune repertoire sequencing data with MiXCR

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