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

Robin J. Dart; Iva Zlatareva; Pierre Vantourout; Efstathios Theodoridis; Ariella Amar; Shichina Kannambath; Philip East; Timothy Recaldin; John C. Mansfield; Christopher A. Lamb; Miles Parkes; Peter M. Irving; Natalie J. Prescott; Adrian C. Hayday

doi:10.1126/science.adh0301

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

Robin J. Dart^*
, Iva Zlatareva
, Pierre Vantourout
, Efstathios Theodoridis
, Ariella Amar
, Shichina Kannambath
, Philip East
, Timothy Recaldin
, John C. Mansfield
, Christopher A. Lamb
, Miles Parkes
, Peter M. Irving
, Natalie J. Prescott
, Adrian C. Hayday^*

^*Corresponding author for this work

GSTT Guy's and St Thomas' NHS Foundation Trust
Immunosurveillance laboratory
Francis Crick Institute
Gastroenterology Department
King's College London
National Institute for Health and Care Research
GammaDelta Therapeutics Ltd
Newcastle University
Royal Victoria Infirmary
Department of Medicine
Department Medical and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

61 Citations (Scopus)

Abstract

Murine intraepithelial gd 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 gd T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset coexpressing T cell receptor Vg4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease, whereas on-treatment CD103+gd T cell restoration was associated with sustained inflammatory bowel disease remission. Moreover, CD103+Vg4+ 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 gd T cells appears to be an evolutionarily conserved axis limiting the progression of a complex, multifactorial, tissue-damaging disease of increasing global incidence.

Original language	English
Article number	adh0301
Journal	Science
Volume	381
Issue number	6663
DOIs	https://doi.org/10.1126/science.adh0301
Publication status	Published - 15 Sept 2023

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Dart, R. J., Zlatareva, I., Vantourout, P., Theodoridis, E., Amar, A., Kannambath, S., East, P., Recaldin, T., Mansfield, J. C., Lamb, C. A., Parkes, M., Irving, P. M., Prescott, N. J., & Hayday, A. C. (2023). Conserved gd T cell selection by BTNL proteins limits progression of human inflammatory bowel disease. Science, 381(6663), Article adh0301. https://doi.org/10.1126/science.adh0301

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title = "Conserved gd T cell selection by BTNL proteins limits progression of human inflammatory bowel disease",

abstract = "Murine intraepithelial gd 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 gd T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset coexpressing T cell receptor Vg4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease, whereas on-treatment CD103+gd T cell restoration was associated with sustained inflammatory bowel disease remission. Moreover, CD103+Vg4+ 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 gd T cells appears to be an evolutionarily conserved axis limiting the progression of a complex, multifactorial, tissue-damaging disease of increasing global incidence.",

author = "Dart, \{Robin J.\} and Iva Zlatareva and Pierre Vantourout and Efstathios Theodoridis and Ariella Amar and Shichina Kannambath and Philip East and Timothy Recaldin and Mansfield, \{John C.\} and Lamb, \{Christopher A.\} and Miles Parkes and Irving, \{Peter M.\} and Prescott, \{Natalie J.\} and Hayday, \{Adrian C.\}",

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AU - Dart, Robin J.

AU - Zlatareva, Iva

AU - Vantourout, Pierre

AU - Theodoridis, Efstathios

AU - Amar, Ariella

AU - Kannambath, Shichina

AU - East, Philip

AU - Recaldin, Timothy

AU - Mansfield, John C.

AU - Lamb, Christopher A.

AU - Parkes, Miles

AU - Irving, Peter M.

AU - Prescott, Natalie J.

AU - Hayday, Adrian C.

PY - 2023/9/15

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N2 - Murine intraepithelial gd 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 gd T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset coexpressing T cell receptor Vg4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease, whereas on-treatment CD103+gd T cell restoration was associated with sustained inflammatory bowel disease remission. Moreover, CD103+Vg4+ 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 gd T cells appears to be an evolutionarily conserved axis limiting the progression of a complex, multifactorial, tissue-damaging disease of increasing global incidence.

AB - Murine intraepithelial gd 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 gd T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset coexpressing T cell receptor Vg4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease, whereas on-treatment CD103+gd T cell restoration was associated with sustained inflammatory bowel disease remission. Moreover, CD103+Vg4+ 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 gd 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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JO - Science

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M1 - adh0301

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

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