The basis of the studies proposed in this project reflect the findings emanating from the initial and longstanding observations in our lab that regulatory T cells are activated following interactions with normal intestinal epithelial cells. These studies also documented defects in CD8+ Treg activation when epithelia cells derived from IBD patients were used to activate T cells. During the course of defining the repertoire of regulatory T cells present in normal and inflamed intestine during the last granting cycle, we identified a novel population of CD4+ FoxP3/IL17 double positive cells in the lamina propria of CD but not UC or normal patients. These cells share phenotypic characteristics of Th17 cells with secretion of IL17, IL22. IL21 while expressing high levels of CCR6, CD161, and RORyt. However, unlike conventional Th17 (cells and similar to FoxP3+ Tregs, they express high levels of CD101 and low levels of CD127, exhibit a similar TcR repertoire (BV usage) and are functionally suppressive in in vitro co-culture systems. FoxP3+IL-17 producing cells are imprinted for gut homing, as indicated by high levels of CCR6, CD103 and the integrin a4B7 expression. These cells secrete IFNy but not IL10 or TGFB. Thus they represent a novel cell population that could provide useful insights into lineage commitment of Tregs versus Th17 cells. We propose that these cells sit at the crossroads between Treg and Th17 cells and that further commitment to either lineage results from microenvironmental cues present in the tissues. The current proposal seeks to characterize these cells and define factors involved in their activation. Most importantly we aim to detemiine the microenvironmental cues that allow these cell to commit to a Th17 (more likely in CD) rather than a regulatory lineage. We will: 1) Define the functional and phenotypic properties of the CD4+ FoxP3/IL17 double positive cells derived from CD;2) Define the microenvironmental cues leading to a transcriptional program that regulates lineage commitment of these cells. In collaboration with Dr. Xiong in Project 3 (IRF8), assess the interactions between FoxP3 and RORyt and determine factors that allow for negative regulation of both transcription factors. 3) Identify counterparts of these cells in murine models of ileitis/colitis or murine infection models in collaboration with Drs. Lira and Blander to establish the conditions required for their generation in vivo.

Public Health Relevance

The studies detailed in this proposal focus on a new T cell population that may have relevance to the development of Crohn's disease. Understanding how this cell gets activated will allow for new insights into therapy of this disease. Understanding how this cell gets activated will allow for new insights into therapy of this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK072201-09
Application #
8730608
Study Section
Special Emphasis Panel (ZDK1-GRB-8)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
9
Fiscal Year
2014
Total Cost
$357,917
Indirect Cost
$146,756
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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