The intestine plays an important role in host protection and immune system modulation. To detect pathogenic organisms a large number of immune cells circulate through the gastrointestinal tract, but the mechanisms underlying the trafficking of immune cells are still poorly understood. A new class of immunoregulatory cells has been recently identified. These cells express the transcriptional regulator RORyt that regulates expression of key cytokines including IL-17 and IL-22, and is critical for differentiation of lymphoid structures in the intestine. In this application we aim to define the mechanisms regulating the development and trafficking of such cells into the intestinal mucosa. These studies are a logical development of our previous application, and build upon our recently published observations on the role of chemokines in the trafficking of cells into the intestine. In addition, we plan to examine the role of IL-23 in the development and function of RORyt+ cells. Genetic studies in humans indicate an association between increased IL-23 signaling and development of IBD. Furthermore, our own transgenic studies show that systemic expression of IL-23 subunit p19 results in severe inflammation. It remains unclear so far if disturbances in IL-23 signaling in the intestine is sufficient to promote inflammation at to what degree this response depends on RORyt+ cells. To address the role of chemokines and IL-23 in the development, trafficking and function of RORyt+ cells in the intestine we will: 1) define the role of chemokines in the distribution of RORyt+ cells in the intestine;2) define the contribution of IL-23 to the development and function of RORyt+ cells during homeostasis and disease.

Public Health Relevance

In this application we aim to define the mechanisms regulating the development, trafficking and function of a specialized group of cells in the intestine. These cells have been shown to produce cytokines that promote inflammatory bowel disease. Our studies will hopefully identify critical factors controlling the migration and activity of such cells and therefore contribute to the development of new treatments for diseases of the intestine.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-8)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
New York
United States
Zip Code
Blander, J Magarian (2016) The comings and goings of MHC class I molecules herald a new dawn in cross-presentation. Immunol Rev 272:65-79
Blander, J Magarian (2016) Death in the intestinal epithelium-basic biology and implications for inflammatory bowel disease. FEBS J 283:2720-30
Campisi, Laura; Barbet, Gaetan; Ding, Yi et al. (2016) Apoptosis in response to microbial infection induces autoreactive TH17 cells. Nat Immunol 17:1084-92
Parkunan, Salai Madhumathi; Randall, C Blake; Astley, Roger A et al. (2016) CXCL1, but not IL-6, significantly impacts intraocular inflammation during infection. J Leukoc Biol 100:1125-1134
Legarda, Diana; Justus, Scott J; Ang, Rosalind L et al. (2016) CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN. Cell Rep 15:2449-61
Ting, Adrian T; Bertrand, Mathieu J M (2016) More to Life than NF-κB in TNFR1 Signaling. Trends Immunol 37:535-45
Roulis, M; Bongers, G; Armaka, M et al. (2016) Host and microbiota interactions are critical for development of murine Crohn's-like ileitis. Mucosal Immunol 9:787-97
Wang, Juan; Peng, Liang; Zhang, Ruihua et al. (2016) 5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation. Oncotarget 7:19312-26
Dong, Xiaonan; Cheng, Adam; Zou, Zhongju et al. (2016) Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis. Proc Natl Acad Sci U S A 113:2994-9
Disteldorf, Erik M; Krebs, Christian F; Paust, Hans-Joachim et al. (2015) CXCL5 drives neutrophil recruitment in TH17-mediated GN. J Am Soc Nephrol 26:55-66

Showing the most recent 10 out of 81 publications