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Title: Activation of CD161-expressing T cells in human blood and gut
Author: Leng, Tianqi
ISNI:       0000 0004 7653 0227
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Human mucosal associated invariant T (MAIT) cells are an important T cell population present in circulation as well as immune privileged sites such as the liver and the gut. They are characterised by a semi-invariant T cell receptor (TCR) and high surface expression levels of CD161 and IL-18Rα, and restriction by the MHC class I-related protein (MR1). Studies have described a broad range of MAIT cell effector functions, including MR1-mediated antibacterial responses and TCR- independent, cytokine-mediated proinflammatory and antiviral properties. How human MAIT cells integrate these signals to exert their effector functions in the gut and in autoimmune and immune-mediated diseases such as inflammatory bowel diseases (IBD) has not been fully described. In this study, an in vitro approach was used to probe MAIT cell activation, and the roles of the TCR, IL-12/-15/-18, TL1A and type I interferons (IFNs). MAIT cells were shown here to achieve certain effector and antimicrobial functions - measured by IFN-γ / tumour necrosis factor-α release and granzyme B expression - with specific innate cytokine signals. These features were reproduced in gut-derived CD8+ MAIT cells and CD161-expressing CD4+ T cells, whose phenotypes and effector functions may not only be mediated by exogenous TCR/cytokine signals, but also tuned by the gut microenvironment and various cues from IBD. Furthermore, while TCR triggering was insufficient to drive full activation, gene expression signatures of TCR-triggered MAIT cells showed specific enrichment of tissue-repair functions, and genome-wide comparison of functional responses to TCR-dependent and -independent signals defined novel functions of MAIT cells relevant not only to host defence but also tissue homeostasis. Overall, these findings indicate the importance of both TCR and inflammatory cytokine signals in promoting effector functions of human CD161-expressing T cells. Further in vitro and in vivo investigations on these gut-derived innate-like CD161+ T cells will be useful to understand their tissue-specific and signal-specific effector functions, as well as their role in various diseases.
Supervisor: Klenerman, Paul ; Willberg, Chris Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available