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

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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Details

Published: Sep 15, 2023
Vol/Issue: 381(6663)

Authors

R

Robin J. Dart

Peter Gorer Department of Immunobiology, King’s College London at Guy’s Hospital Campus, London, UK.; Immunosurveillance Laboratory, The Francis Crick Institute, London, UK.; Department of Gastroenterology, Guy’s and St Thomas’ Foundation Trust, London, UK.

I

Iva Zlatareva

Peter Gorer Department of Immunobiology, King’s College London at Guy’s Hospital Campus, London, UK.; Immunosurveillance Laboratory, The Francis Crick Institute, London, UK.

P

Pierre Vantourout

Peter Gorer Department of Immunobiology, King’s College London at Guy’s Hospital Campus, London, UK.; Immunosurveillance Laboratory, The Francis Crick Institute, London, UK.

E

Efstathios Theodoridis

Peter Gorer Department of Immunobiology, King’s College London at Guy’s Hospital Campus, London, UK.; Immunosurveillance Laboratory, The Francis Crick Institute, London, UK.

A

Ariella Amar

Department of Medical and Molecular Genetics, King’s College London, London, UK.

S

Shichina Kannambath

National Institute for Health and Care Research (NIHR) Biomedical Research Centre (BRC) Genomics Centre, King’s College London, London, UK.

P

Philip East

Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK.

T

Timothy Recaldin

GammaDelta Therapeutics Ltd., London, UK.

J

John C. Mansfield

Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.; Department of Gastroenterology, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Royal Victoria Infirmary, Newcastle upon Tyne, UK.

C

Christopher A. Lamb

Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.; Department of Gastroenterology, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Royal Victoria Infirmary, Newcastle upon Tyne, UK.

M

Miles Parkes

Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK.

P

Peter M. Irving

Department of Gastroenterology, Guy’s and St Thomas’ Foundation Trust, London, UK.

N

Natalie J. Prescott

Department of Medical and Molecular Genetics, King’s College London, London, UK.

A

Adrian C. Hayday

Peter Gorer Department of Immunobiology, King’s College London at Guy’s Hospital Campus, London, UK.; Immunosurveillance Laboratory, The Francis Crick Institute, London, UK.

Cite This Article

Robin J. Dart, Iva Zlatareva, Pierre Vantourout, et al. (2023). Conserved γδ T cell selection by BTNL proteins limits progression of human inflammatory bowel disease. Science, 381(6663). https://doi.org/10.1126/science.adh0301

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

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