This is an application for an extension of a MERIT award to study natural killer T cells (NKT cells). Evidence of progress during the previous funding period is supported by 30 publications. Some of the main published findings were;1) Determination that NKT cells can be activated independently of antigen presentation, particularly in the presence of IL-12. This mechanism allows NKT cells to become activated during viral Infections. 2) The identification of antigens from pathogenic Borrelia burgdorferi spirochetes that can activate NKT cells. These glycolipid antigens have diacylglycerol as the lipid moiety, a lipid that is found in many pathogenic microbes. We showed that NKT cells are important for preventing arthritis in a mouse model of Lyme disease. 3) We have described a mechanism for the THI skewiing of NKT cell cytokine responses that is not dependent on TCR affinity, but which is dependent on increased antigenic stability in vivo. This finding may aid in the development of new ligands for NKT cell activation. In the extension period, we will invesitgate the transcriptional control of Thi and Th2 cytokine synthesis by NKT cells. We also will analyze how NKT cells contribute to host defense in the lung following infection with S. pneumoniae. Additionally, we will explore how components of the autophagy machinery influence NKT cell differentiation and CD1d antigen presentation.

Public Health Relevance

NKT cells are a unique lymphocyte population that combine features ofthe innate and adaptive immunity. They have been reported to influence many types of immune responses, and activation of NKT cells is being explored as a potential cancer immune therapy. Our experimental results will help our understanding as to how these cells function in immune protection, which may lead to new immune therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Miller, Lara R
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La Jolla Institute
La Jolla
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Sag, Duygu; Özkan, Müge; Kronenberg, Mitchell et al. (2017) Improved Detection of Cytokines Produced by Invariant NKT Cells. Sci Rep 7:16607
Engel, Isaac; Seumois, Grégory; Chavez, Lukas et al. (2016) Innate-like functions of natural killer T cell subsets result from highly divergent gene programs. Nat Immunol 17:728-39
Crosby, Catherine M; Kronenberg, Mitchell (2016) Invariant natural killer T cells: front line fighters in the war against pathogenic microbes. Immunogenetics 68:639-48
Birkholz, Alysia M; Howell, Amy R; Kronenberg, Mitchell (2015) The Alpha and Omega of Galactosylceramides in T Cell Immune Function. J Biol Chem 290:15365-70
Pei, Bo; Zhao, Meng; Miller, Brian C et al. (2015) Invariant NKT cells require autophagy to coordinate proliferation and survival signals during differentiation. J Immunol 194:5872-84
Chandra, Shilpi; Kronenberg, Mitchell (2015) Activation and Function of iNKT and MAIT Cells. Adv Immunol 127:145-201
Birkholz, Alysia M; Girardi, Enrico; Wingender, Gerhard et al. (2015) A Novel Glycolipid Antigen for NKT Cells That Preferentially Induces IFN-? Production. J Immunol 195:924-33
Wingender, Gerhard; Birkholz, Alysia M; Sag, Duygu et al. (2015) Selective Conditions Are Required for the Induction of Invariant NKT Cell Hyporesponsiveness by Antigenic Stimulation. J Immunol 195:3838-48
Birkholz, Alysia; Nem?ovi?, Marek; Yu, Esther Dawen et al. (2015) Lipid and Carbohydrate Modifications of ?-Galactosylceramide Differently Influence Mouse and Human Type I Natural Killer T Cell Activation. J Biol Chem 290:17206-17
Chandra, Shilpi; Zhao, Meng; Budelsky, Alison et al. (2015) A new mouse strain for the analysis of invariant NKT cell function. Nat Immunol 16:799-800

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