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Defining the role of NCR- ILC3s in chronic colitis

Student thesis: Doctoral ThesisDoctor of Philosophy

Innate lymphoid cells (ILCs) are relatively newly identified cells that have a lymphoid-like morphology, but lack antigen specific receptors. Similarly to T cells, they can be divided into three main groups (1, 2 and 3), which produce distinct combinations of cytokines to mediate their functions, and whose development depends on different transcriptional factors. Group 3 ILCs (ILC3s) are enriched at mucosal surfaces, where they act as key effector cells. They can be further subdivided into lymphoid tissue inducer (LTi) cells, and NCR+ or NCR- ILC3s based on whether or not they express natural cytotoxicity receptors. NCR- ILC3s, which co-produce IL-22 and IL-17A, remain poorly understood, especially with regards to their function in the colon.
In this thesis it was shown that NCR- ILC3s were the dominant ILC3 subset in the healthy colon, as well as during colonic inflammation, and that NCR- ILC3s drived colitis in Tbx21-/- x Rag2-/- Ulcerative Colitis (TRUC) mice with IL-22 being their effector cytokine. NCR- ILC3 derived IL-22 triggered endoplasmic reticulum (ER) stress in colonic epithelial cells and induced CXCL1 and CXCL5 secretion that subsequently led to neutrophil recruitment to the inflamed colon. These pro-inflammatory actions of IL-22 were augmented by IL-17A, another cytokine produced by NCR- ILC3s that is strongly implicated in inflammatory bowel disease (IBD) pathogenesis. Whole transcriptome analysis of colonic biopsies from patients with Ulcerative colitis (UC) and healthy individuals revealed compelling evidence that these pro-inflammatory, IL-22 dependent pathways may be relevant in human disease.
Taken all together these data shed more light into TRUC disease, and possibly provides new insights into the immunopathology of chronic colitis. Targeting the pro-inflammatory pathways mediated by NCR- ILC3s may represent a novel therapeutic approach for IBD.
Original languageEnglish
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Award date2018

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