Mucosal surfaces such as the intestinal epithelium provide a complex challenge to the immune system, as they must maintain effective immunity against potential pathogen attack while also tolerating commensal microorganisms and dietary antigens. The balance between tolerance and immunity is mediated in large part by the specialized T cell populations, regulatory T cells (Tregs) and Th17 cells. Disruption of the balance between these subsets has been heavily implicated in causing colitis through studies in both mice and humans. Furthermore, Th17 cells are emerging as contributors to many other inflammatory and autoimmune disorders. Understanding how Th17 responses are initiated and regulated is therefore critical to our understanding of both intestinal immunity and chronic inflammatory disease. Our long term goal is to understand how Dendritic Cells (DCs) and other antigen presenting cells initiate and maintain the correct balance of T-helper cell subsets. The objective in this application is to establish how DCs regulate T cell responses to TGF-? and control Th17 cell differentiation. The rationale for this work is that understanding this process has the potential to translate into new therapies for Th17-mediated diseases. Our central hypothesis is that DC expression of ?v?8 and subsequent activation of TGF-? controls induction and maintenance of Th17 responses. Based on published work and preliminary data, this hypothesis will be tested in three specific aims: (1) Determine how ?v integrins expressed by DCs regulate Th17 cell differentiation, particularly the generation of IL17/ IFN-?-expressing cells associated with autoimmunity. Conditional knockout mice will be used to study the role for ?v integrins in vivo, and results will be extended to humans though primary cell culture. (2) Understand how ?8 expression is regulated in DCs during homeostatic regulation and following infection. (3) Determine the mechanisms by which ?v?8 function is regulated on DCs using cell biology and biochemical approaches. This approach is innovative as it focuses on the role of DCs in 'licensing'T cell responses to TGF-?. The proposed work is significant because it will provide a much needed understanding of how DCs promote the initiation of Th17 cells in the intestine and regulate their subsequent differentiation in response to environmental and infectious challenges.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093695-04
Application #
8690042
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2012-07-05
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98101
Acharya, Mridu; Sokolovska, Anna; Tam, Jenny M et al. (2016) αv Integrins combine with LC3 and atg5 to regulate Toll-like receptor signalling in B cells. Nat Commun 7:10917
Boucard-Jourdin, Mathilde; Kugler, David; Endale Ahanda, Marie-Laure et al. (2016) β8 Integrin Expression and Activation of TGF-β by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage. J Immunol 197:1968-78
Du, Fang; Garg, Abhishek V; Kosar, Karis et al. (2016) Inflammatory Th17 Cells Express Integrin αvβ3 for Pathogenic Function. Cell Rep 16:1339-51
Tam, Jenny M; Mansour, Michael K; Acharya, Mridu et al. (2016) The Role of Autophagy-Related Proteins in Candida albicans Infections. Pathogens 5:
Lee, Hye Shin; Cheerathodi, Mujeeburahiman; Chaki, Sankar P et al. (2015) Protein tyrosine phosphatase-PEST and β8 integrin regulate spatiotemporal patterns of RhoGDI1 activation in migrating cells. Mol Cell Biol 35:1401-13
Tam, Jenny M; Mansour, Michael K; Khan, Nida S et al. (2014) Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages. J Infect Dis 210:1844-54
Kaneko, Keiko; Ito, Masako; Naoe, Yoshinori et al. (2014) Integrin αv in the mechanical response of osteoblast lineage cells. Biochem Biophys Res Commun 447:352-7
Overstreet, Michael G; Gaylo, Alison; Angermann, Bastian R et al. (2013) Inflammation-induced interstitial migration of effector CD4⁺ T cells is dependent on integrin αV. Nat Immunol 14:949-58
Henderson, Neil C; Arnold, Thomas D; Katamura, Yoshio et al. (2013) Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 19:1617-24
Sokolovska, Anna; Becker, Christine E; Ip, W K Eddie et al. (2013) Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function. Nat Immunol 14:543-53

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