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; Sundling, Christopher; Färnert, Anna; Bernhardsson, Carolina; Larena, Maximilian; Jakobsson, Mattias; Hedestam, Gunilla B. Karlsson

doi:10.1101/2022.08.25.505097

Cited by 4 publications

(6 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, the only clearly established biochemical function of BTNL3+8 heteromers and their mouse counterparts is to engage intestinal gd TCR Vg chains. Direct evidence germane to the importance of CD103 + Vg4 + 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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Importantly the corecount program is not restricted to IgM libraries. It can also be used for IgK and IgL genotyping, as well as for TRA, TRB, TRG and TRD genotyping ( 36 ). It is important to note, however, that since corecount utilizes exact matches to expressed sequences, it requires libraries with a substantial proportion of unmutated sequences and so IgG libraries will not be suitable.…”

Section: Discussionmentioning

confidence: 99%

Adaptive immune receptor genotyping using the corecount program

et al. 2023

Self Cite

View full text Add to dashboard Cite

We present a new Rep-Seq analysis tool called corecount, for analyzing genotypic variation in immunoglobulin (IG) and T cell receptor (TCR) genes. corecount is highly efficient at identifying V alleles, including those that are infrequently used in expressed repertoires and those that contain 3’ end variation that are otherwise refractory to reliable identification during germline inference from expressed libraries. Furthermore, corecount facilitates accurate D and J gene genotyping. The output is highly reproducible and facilitates the comparison of genotypes from multiple individuals, such as those from clinical cohorts. Here, we applied corecount to the genotypic analysis of IgM libraries from 16 individuals. To demonstrate the accuracy of corecount, we Sanger sequenced all the heavy chain IG alleles (65 IGHV, 27 IGHD and 7 IGHJ) from one individual from whom we also produced two independent IgM Rep-seq datasets. Genomic analysis revealed that 5 known IGHV and 2 IGHJ sequences are truncated in current reference databases. This dataset of genomically validated alleles and IgM libraries from the same individual provides a useful resource for benchmarking other bioinformatic programs that involve V, D and J assignments and germline inference, and may facilitate the development of AIRR-Seq analysis tools that can take benefit from the availability of more comprehensive reference databases.

show abstract

“…Prima facie, these outcomes have some parallels with BTNL-mediated, Vγ-dependent activation of γδ TCRs that at early times of development induces targeted cells to proliferate and establish stable residency in extralymphoid niches, wherein they share with memory T cells a capacity for rapid effector responsiveness, enhanced by signaling from innate receptors, e.g., NKG2D (21)(22)(23)57). It therefore seems reasonable to speculate that nonclonotypic signals received selectively via innate TRBV motifs, albeit via asyet unidentified self or microbial ligands, might contribute to shaping complex human germline TRBV repertoires (12,58). Although BTNL engagement does not induce significant increases in effector functions (GZMB and IFN-γ) (22) as is seen for anti-TRBV-stimulated αβ T cells, it does strongly skew cells toward a Tc1/T H 1 phenotype when the cells are subsequently activated (59,60).…”

Section: Discussionmentioning

confidence: 99%

Innate TCRβ-chain engagement drives human T cells toward distinct memory-like effector phenotypes with immunotherapeutic potentials

Vantourout,

Eum,

Conde Poole

et al. 2023

Sci. Adv.

View full text Add to dashboard Cite

Clonotypic αβ T cell responses to cargoes presented by major histocompatibility complex (MHC), MR1, or CD1 proteins underpin adaptive immunity. Those responses are mostly mediated by complementarity-determining region 3 motifs created by quasi-random T cell receptor (TCR) gene rearrangements, with diversity being highest for TCRγδ. Nonetheless, TCRγδ also displays nonclonotypic innate responsiveness following engagement of germline-encoded Vγ-specific residues by butyrophilin (BTN) or BTN-like (BTNL) proteins that uniquely mediate γδ T cell subset selection. We now report that nonclonotypic TCR engagement likewise induces distinct phenotypes in TCRαβ + cells. Specifically, antibodies to germline-encoded human TCRVβ motifs consistently activated naïve or memory T cells toward core states distinct from those induced by anti-CD3 or superantigens and from others commonly reported. Those states combined selective proliferation and effector function with activation-induced inhibitory receptors and memory differentiation. Thus, nonclonotypic TCRVβ targeting broadens our perspectives on human T cell response modes and might offer ways to induce clinically beneficial phenotypes in defined T cell subsets.

show abstract

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

Cited by 4 publications

References 62 publications

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

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

Adaptive immune receptor genotyping using the corecount program

Innate TCRβ-chain engagement drives human T cells toward distinct memory-like effector phenotypes with immunotherapeutic potentials

Contact Info

Product

Resources

About