Role of group 2 innate lymphoid cells and SHIP-1 in mucosal immunity

• Main Author: Gold, Matthew Joshua
• Language: English
• Published: University of British Columbia 2015
• Online Access: http://hdl.handle.net/2429/51891

Mucosal surfaces present an important barrier between the host and environment. Maintenance of barrier function requires intricate cross-talk between a diverse array of immune cells and the epithelia, acting synergistically to respond to harmful antigens and maintain tolerance to innocuous antigens. In this thesis I utilized an array of transgenic animals to explore the cellular and molecular mechanisms that initiate adaptive immune responses in the lung and gut mucosa. Recently, innate lymphoid cells have been characterized for their role in maintaining barrier immunity. Group 2 innate lymphoid cells (ILC2s) colonize the lung and provide a rapid source of IL-5 and IL-13 in a T and B cell independent manner in response to protease antigens. Using ILC2-deficient mice, I examined the role of these cells in mucosal inflammation using mouse models of allergic asthma and hypersensitivity pneumonitis (HP). ILC2s were critical in initiation of a Th2 response to locally, but not systemically delivered allergens and were completely dispensable for Th1 and Th17 dependent responses. The PI3K pathway plays an important role in regulating leukocyte activation, survival, migration and cytokine release. It is negatively regulated by the lipid phosphatase Ship1, and Ship1-/- mice develop a wide array of hematological disorders leading to a reduced lifespan. The severe phenotype associated with loss of Ship1 throughout the immune systems masks subtler roles it plays in specific leukocyte subsets. Using a conditional deletion approach, I examined the role of Ship1 in T cells, B cells and dendritic cells (DCs) in mouse models of allergic asthma and helminth infection. While loss of Ship1 in B cells did not influence susceptibility to a HDM model of allergic asthma, loss of Ship1 in either the T cells or DCs protected from disease development due to an immune skewing to a Th1 response. Additionally, loss of Ship1 in DCs rendered mice susceptible to infection with the intestinal helminth Trichuris muris, further highlighting this Th1 immune skewing. === Medicine, Faculty of === Medicine, Department of === Experimental Medicine, Division of === Graduate