Doherty Institute - Theses
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ItemRole of mucosal-associated invariant T (MAIT) cells in Helicobacter pylori infection( 2017)Helicobacter pylori infects the human stomach of approximately half the world’s population and is aetiologically associated with a range of pathologies including gastritis, duodenal ulcers and gastric cancer. The development of severe disease depends on a complex interplay of the host immune system, bacterial virulence factors and environmental factors. A key feature that determines which H. pylori positive individuals develop disease is the severity of inflammation. Mucosal-associated Invariant T (MAIT) cells are innate like T cells that are restricted by the non-classical MHC class I-related molecule, MR1. MAIT cells detect antigens that are derived from microbial vitamin B2 (riboflavin) synthesis, and produce inflammatory cytokines, including IL17, IFNγ and TNF, and cytotoxic granzymes. Although MAIT cells have been shown to be protective against some pulmonary infections, their production of pro-inflammatory cytokines suggest chronic stimulation of MAIT cells could contribute to pathology. The studies presented in this thesis aimed to understand the role of MAIT cells in the development of gastritis during H. pylori infection and identify the mechanisms by which MAIT cells perform this role. Using highly specific MR1 tetramers and mouse models of H. pylori infection, it was shown that MAIT cells accumulate in the stomach and accelerate pathology. This occurred both in MAIT TCR transgenic mice, and in a prime-boost model of C57BL/6 mice where MAIT cells were first primed intranasally either with Salmonella Typhimurium or with TLR agonist plus synthetic antigen. MAIT cells have the ability to recruit other T cells and innate immune cells that then help precipitate disease and exacerbate inflammation leading to atrophic gastritis. The results in this thesis also demonstrate that the riboflavin pathway is essential for MAIT TCR based stimulation and that neither antigen alone nor TLR agonist alone can induce MAIT cell expansion, suggesting a co-stimulus either in the form of bacterial infection or TLR stimulation is essential for MAIT cell expansion and induction of pathology on H. pylori infection. MAIT TCR repertoire analysis revealed that the TCR repertoire does not change dramatically post infection with either S. Typhimurium in the lung or H. pylori infection in the stomach, suggesting shared antigen specificity. In summary, the studies in this thesis demonstrated a pathogenic role for MAIT cells for the first time in Helicobacter-associated inflammation. These findings add to our understanding of MAIT cells and implicate MAIT cells in chronic inflammation, and will help develop therapeutic strategies to target these cells in inflammatory disorders.