This renewal application seeks support for the continuation of our studies designed to elucidate the regulatory programs of dendritic cell subsets that are required for antimicrobial host defenses in the intestine. We recently discovered a cellular circuitry, whereby mucosal DCs interact with the fenestrated capillary vessel system of the small intestine for the sampling of antigens that transition from the blood circulation through the lamina propria into the intestinal lymphatic system and the control of mucosal inflammation. The integration of luminal and circulatory antigen surveillance in the SI indicates that mucosal dendritic cells and macrophages could receive microbial signals that originate outside the intestine and that intestinal pathogen recognition could impact peripheral immune responses. The focus of this proposal will be the foreign nucleic acid recognition pathways in mucosal Zbtb46+ DCs that include distinct classical DC subsets that can induce IL-17 expressing T helper cells (Th17) cells in the mucosal immune system but also drive inducible T regulatory cell development and IL-10 expression. Defining these pivotal mechanisms is important for strategies that can control intestinal inflammation but also for the understanding of the impact of mucosal immune responses on the peripheral immune system and extra intestinal manifestation of inflammatory bowel diseases.

Public Health Relevance

A detailed understanding of sensing of microbial components by dendritic cells in the intestine for the induction of host defenses or tolerance is critical for strategies to curtail mechanisms that impede or exacerbate mucosal immune responses leading to Inflammatory Bowel Diseases. We aim to unravel mechanisms that control the differentiation of mucosal dendritic cells for the regulation of host defenses against viral and bacterial pathogens by elucidating the transcriptional programs that determine T cell polarization in the intestinal mucosa and mesenteric lymph nodes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Mohanan, Vishnu; Nakata, Toru; Desch, A Nicole et al. (2018) C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions. Science 359:1161-1166
Kim, Young-In; Song, Joo-Hye; Ko, Hyun-Jeong et al. (2018) CX3CR1+ Macrophages and CD8+ T Cells Control Intestinal IgA Production. J Immunol 201:1287-1294
Maldonado-Contreras, Ana; Birtley, James R; Boll, Erik et al. (2017) Shigella depends on SepA to destabilize the intestinal epithelial integrity via cofilin activation. Gut Microbes 8:544-560
Ravindran, Ethiraj; Hu, Hao; Yuzwa, Scott A et al. (2017) Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation. PLoS Genet 13:e1006746
Bouziat, Romain; Hinterleitner, Reinhard; Brown, Judy J et al. (2017) Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356:44-50
Li, Yang; Basavappa, Megha; Lu, Jinfeng et al. (2016) Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells. Nat Microbiol 2:16250
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
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
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
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

Showing the most recent 10 out of 33 publications