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
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

Showing the most recent 10 out of 28 publications