These studies will provide new insights into the region specific regulatory programs of DCs in mucosal surfaces. We have identified a mucosal plasmacytoid dendritic cell (pDC) subset that has a critical role in limiting intestinal inflammation thereby promoting tissue reconstruction and mucosal restitution. This pDC subset appears as a major DC subset in the intestine during colitis to direct mucosa-specific T cell functions essential for the resolution of inflammation. We hypothesize that mucosal pDCs are principal mediators of mucosal repair responses by controlling the intestine-specific regulatory phenotypes of Foxp3+ Tregs and Th17 cells. We will define key mechanisms that allow regulatory mucosal pDCs to effectively suppress inflammatory signals and to mediate mucosal protection. Defining the functional role of this newly discovered pDC subset in the regulation of mucosal inflammation will provide pivotal insights into the mechanisms that mediate mucosa specific control of regulatory T cells required for tissue repair in the highly antigenic environment of the intestine.

Public Health Relevance

A more precise definition of the function of specialized dendritic cells in the regulation of mucosal T cells is required for our understanding of the mechanisms which control intestinal inflammation. We will define the functional role of a newly discovered mucosal dendritic cell subset in the regulation of mucosal inflammation to provide pivotal insights into the mechanisms that mediate mucosa-specific control of regulatory T cells required for tissue repair.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068181-06
Application #
8244521
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Carrington, Jill L
Project Start
2004-07-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$363,602
Indirect Cost
$158,177
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Lammers, Karen M; Chieppa, Marcello; Liu, Lunhua et al. (2015) Gliadin Induces Neutrophil Migration via Engagement of the Formyl Peptide Receptor, FPR1. PLoS One 10:e0138338
O'Keeffe, Michael S; Song, Joo-Hye; Liao, Gongxian et al. (2015) SLAMF4 Is a Negative Regulator of Expansion of Cytotoxic Intraepithelial CD8+ T Cells That Maintains Homeostasis in the Small Intestine. Gastroenterology 148:991-1001.e4
Liao, Gongxian; O'Keeffe, Michael S; Wang, Guoxing et al. (2014) Glucocorticoid-Induced TNF Receptor Family-Related Protein Ligand is Requisite for Optimal Functioning of Regulatory CD4(+) T Cells. Front Immunol 5:35
Dasgupta, Suryasarathi; Erturk-Hasdemir, Deniz; Ochoa-Reparaz, Javier et al. (2014) Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host Microbe 15:413-23
Chiang, Hao-Sen; Zhao, Yun; Song, Joo-Hye et al. (2014) GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses. Nat Immunol 15:63-71
Sundberg, Thomas B; Choi, Hwan Geun; Song, Joo-Hye et al. (2014) Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells. Proc Natl Acad Sci U S A 111:12468-73
Lee, In-Ah; Low, Daren; Kamba, Alan et al. (2014) Oral caffeine administration ameliorates acute colitis by suppressing chitinase 3-like 1 expression in intestinal epithelial cells. J Gastroenterol 49:1206-16
Chang, Sun-Young; Song, Joo-Hye; Guleng, Bayasi et al. (2013) Circulatory antigen processing by mucosal dendritic cells controls CD8(+) T cell activation. Immunity 38:153-65
Low, Daren; Tran, Hoa T; Lee, In-Ah et al. (2013) Chitin-binding domains of Escherichia coli ChiA mediate interactions with intestinal epithelial cells in mice with colitis. Gastroenterology 145:602-12.e9
Conway, Kara L; Kuballa, Petric; Song, Joo-Hye et al. (2013) Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology 145:1347-57

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