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Title: The human colonic γδ T cell compartment and its regulation by butyrophilin-like molecules in health and inflammatory bowel disease
Author: Dart, Robin John Campbell
ISNI:       0000 0004 7970 0789
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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The human intestine is covered by a monocellular epithelial layer forming the barrier between the intestinal lumen and the host. Whilst performing vital absorptive, and protective functions, the epithelium also harbours a specialised subset of intraepithelial lymphocytes (IEL) which have roles in epithelial maintenance and host protection. Despite intense study of the human colonic mucosal immune system in the setting of intestinal immunopathology, the precise roles of colonic IEL, many of which express the γδ T cell receptor (TCR), have remained enigmatic. Whereas intestinal TCRγδ+ IEL have mostly been studied in mice, their conservation and relevance to human colonic IEL has commonly been questioned. Employing novel isolation techniques, this study demonstrates a significant γδ T cell compartment in the human colon which can be isolated for further studies. Thereby, the study shows that the selective regulation of signature, murine Vγ7+ IEL by tissuespecific butyrophilin-like (Btnl) proteins is strikingly conserved in humans. Specifically, human BTNL3 and BTNL8 act together to elicit specific TCR-dependent responses from human Vγ4+ T cells which are shown to compose a major subset of TCRγδ+ IEL in the healthy human colon. Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is characterized by epithelial dysregulation. This study shows that in IBD, colonic gd IEL are commonly and overtly dysregulated in terms of cell phenotype; TCR usage; and the responsiveness of Vg4+ cells to tissue-specific BTNLs. In a number of donors such strikingly dysregulated Vg4+ cell responsiveness is shown to be associated with either of two BTNL gene polymorphisms. These polymorphisms are subsequently assessed via a large case-controlled study as to whether they are associated with susceptibility to CD. In summary, by characterising and comparing the colonic  γδ T cell immunophenotype in health and disease, this study has implicated communication between epithelial cells and IEL as a key axis in IBD, with implications for the understanding of intestine immunopathology and for the basic biology of  γδ T cells.
Supervisor: Hayday, Adrian Clive ; Peakman, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available