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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Tyznik, Aaron J; Verma, Shilpi; Wang, Qiao et al. (2014) Distinct requirements for activation of NKT and NK cells during viral infection. J Immunol 192:3676-85
Wu, Dennis J; Zhou, Wenbo; Enouz, Sarah et al. (2014) Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells. PLoS One 9:e86677
Holzapfel, Keli L; Tyznik, Aaron J; Kronenberg, Mitchell et al. (2014) Antigen-dependent versus -independent activation of invariant NKT cells during infection. J Immunol 192:5490-8
Wang, J J; Yang, G-X; Zhang, W C et al. (2014) Escherichia coli infection induces autoimmune cholangitis and anti-mitochondrial antibodies in non-obese diabetic (NOD).B6 (Idd10/Idd18) mice. Clin Exp Immunol 175:192-201
Kain, Lisa; Webb, Bill; Anderson, Brian L et al. (2014) The identification of the endogenous ligands of natural killer T cells reveals the presence of mammalian ?-linked glycosylceramides. Immunity 41:543-54
Kronenberg, Mitchell; Havran, Wendy L (2014) Immunology: oiling the wheels of autoimmunity. Nature 506:42-3
Sag, Duygu; Krause, Petra; Hedrick, Catherine C et al. (2014) IL-10-producing NKT10 cells are a distinct regulatory invariant NKT cell subset. J Clin Invest 124:3725-40
Kawasaki, Norihito; Vela, Jose Luis; Nycholat, Corwin M et al. (2013) Targeted delivery of lipid antigen to macrophages via the CD169/sialoadhesin endocytic pathway induces robust invariant natural killer T cell activation. Proc Natl Acad Sci U S A 110:7826-31
Kinjo, Yuki; Kitano, Naoki; Kronenberg, Mitchell (2013) The role of invariant natural killer T cells in microbial immunity. J Infect Chemother 19:560-70
Wingender, Gerhard; Stepniak, Dariusz; Krebs, Philippe et al. (2012) Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice. Gastroenterology 143:418-28

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