NKT cells are CD1d-restricted immunoregulatory T cells that bridge between innate and adaptive immunity. Two subsets of NKT cells have been identified, invariant NKT (iNKT) cells that express an invariant V?14-J?18 TCR ? chain and variant NKT (vNKT) with a more diverse TCR repertoire. iNKT cells have been extensively studied, playing an important role in autoimmune disease, infection and tumor immunity. Their early response and rapid secretion of both TH1 and TH2 cytokines, as well as lack of memory response, highlights the innate-like function of these cells. The activation and function of vNKT cells, on the other hand, remain relatively unexplored. This proposal seeks to compare and contrast the diversity and function of both iNKT and vNKT cells in response to altered CD1d expression and allelic differences in CD1d as well as determine the molecular mechanisms governing selection and development of these cell types. First, we will use spontaneous liver pathology in CD1d transgenic mice to examine whether and how altered CD1d expression pattern affects the function of both iNKT and vNKT cells. We will also explore how downstream effects of this altered function result in the spontaneous chronic liver disease. Secondly, we will use CD1 congenic mice as a model to study the diversity, antigen presentation requirements, and potential memory response of vNKT cells as compared to iNKT cells. Thirdly, we will use Elf-1-deficient mice, which are selectively impaired in NKT cell development, as a model to study how ETS family transcription factors may regulate the development and function of NKT cells. As both subsets of NKT cell are present in humans, our studies on the development, regulation and function of these unique T cell populations will provide a better understanding of the comparative contributions of these cell types in normal and pathological immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043407-14
Application #
8111983
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Miller, Lara R
Project Start
1998-08-01
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2014-07-31
Support Year
14
Fiscal Year
2011
Total Cost
$326,663
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Weng, Xiufang; He, Ying; Visvabharathy, Lavanya et al. (2017) Crosstalk between type II NKT cells and T cells leads to spontaneous chronic inflammatory liver disease. J Hepatol 67:791-800
Wang, Yajun; Yun, Chawon; Gao, Beixue et al. (2017) The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation. Cell Rep 20:600-612
O'Hagan, Kyle L; Zhao, Jie; Pryshchep, Olga et al. (2015) Pak2 Controls Acquisition of NKT Cell Fate by Regulating Expression of the Transcription Factors PLZF and Egr2. J Immunol 195:5272-84
Siddiqui, Sarah; Visvabharathy, Lavanya; Wang, Chyung-Ru (2015) Role of Group 1 CD1-Restricted T Cells in Infectious Disease. Front Immunol 6:337
Zhao, Jie; Weng, Xiufang; Bagchi, Sreya et al. (2014) Polyclonal type II natural killer T cells require PLZF and SAP for their development and contribute to CpG-mediated antitumor response. Proc Natl Acad Sci U S A 111:2674-9
Weng, Xiufang; Liao, Chia-Min; Bagchi, Sreya et al. (2014) The adaptor protein SAP regulates type II NKT-cell development, cytokine production, and cytotoxicity against lymphoma. Eur J Immunol 44:3646-57
Zhao, Jie; Bagchi, Sreya; Wang, Chyung-Ru (2014) Type II natural killer T cells foster the antitumor activity of CpG-oligodeoxynucleotides. Oncoimmunology 3:e28977
Liao, Chia-Min; Zimmer, Michael I; Wang, Chyung-Ru (2013) The functions of type I and type II natural killer T cells in inflammatory bowel diseases. Inflamm Bowel Dis 19:1330-8
Liao, Chia-Min; Zimmer, Michael I; Shanmuganad, Sharmila et al. (2012) dysregulation of CD1d-restricted type ii natural killer T cells leads to spontaneous development of colitis in mice. Gastroenterology 142:326-34.e1-2
Choi, Hak-Jong; Geng, Yanbiao; Cho, Hoonsik et al. (2011) Differential requirements for the Ets transcription factor Elf-1 in the development of NKT cells and NK cells. Blood 117:1880-7

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