CD1d-restricted natural killer T (NKT) cells are a distinct subset of T cells that rapidly produce an array of cytokines upon activation and play a critical role in regulating various immune responses. NKT cells are classified into two groups based on differences in T cell receptor usage. Type I NKT cells otherwise known as invariant NKT (iNKT) cells, have an invariant TCR ?-chain and are readily detectable by ?-galactosylceramide (?-GalCer)-loaded CD1d tetramers. Type II NKT cells or variant NKT cells have a more diverse TCR repertoire. While both NKT cell subsets are thought to be immunoregulatory in nature, contrasting roles of iNKT and type II NKT cells in tumor immunity have been described. The distinct functional capabilities may be attributed to distinct developmental features or unique antigen recognition. Unlike iNKT cells, little is known about thymic selection and functional regulation of type II NKT cells due to a lack of surface markers specific to this subset.
In Aim 1 of this proposal, we propose to use a new animal model to identify the cell type(s) that mediate positive selection of type II NKT cells. Since altered CD1d expression has been reported under various inflammatory conditions, we also propose to investigate the effect of increased CD1d expression on the activation and function of type II NKT cells. These studies will provide information on the similarities and differences in thymic selection and peripheral activation of these two NKT cell subsets. Recent studies have found that metabolic state is extremely important for the function of conventional T cells. In particular mitochondrial function appears to play an important role in the generation of memory CD8+ T cells. Unlike conventional T cells, NKT cells exhibit an activated/memory phenotype in naive mice with several transcription factors and signaling pathways uniquely required for the development of this T cell subset. However, it is not clear whether NKT cells have distinct metabolic requirements for their development and function. To begin investigating this issue in Aim 2 of this proposal, we will utilize mice that have mitochondrial metabolic genes conditionally deleted in T cells to elucidate the role of mitochondrial metabolism in the development and function of both NKT cell subsets.
In Aim 3, we propose to characterize the metabolic profiles of iNKT cells and type II NKT cells in their resting and activated states to test the hypothesis that lack of apparent iNKT memory responses may be in part due to the inability of iNKT cells to increase mitochondrial metabolism. Collectively, these studies will provide information on whether metabolic manipulation can enhance the immunotherapies that target NKT cells.

Public Health Relevance

Natural Killer T (NKT) cells play an important regulatory role in the immune system, in particular determining the functional outcome of other major immune cells. The current proposal will use novel mouse models to study how these T cell are activated and how mitochondrial metabolism regulates their development and function. Findings from these experiments may help fine-tuning NKT cell based therapeutic strategies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Innate Immunity and Inflammation Study Section (III)
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Miller, Lara R
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Northwestern University at Chicago
Schools of Medicine
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Bagchi, Sreya; Genardi, Samantha; Wang, Chyung-Ru (2018) Linking CD1-Restricted T Cells With Autoimmunity and Dyslipidemia: Lipid Levels Matter. Front Immunol 9:1616
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

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