Both NK and T cells are important in defense against infections and tumors. The overall goal of this application is to study the physiologically relevant factors controlling NK and T cell responses in vivo. The work proposed is based on our previous characterization of NK and T cell activation and proliferation during murine infections with lymphocytic choriomeningitis virus (LCMV) and in response to treatments with the chemical inducers of interferon (IFC), polyinosinic-polycytidylic acid (poly I:C), IFNs, or interleukin-2(IL-2). Those studies showed that NK cell blastogenesis and proliferation are induced in response to IFNs and at early times post-infection. In contrast, T cell activation and proliferation occur at late times post-infection. Expression and function of IFNs, IL-2, and transforming growth factor-beta (TGF-beta) have been examined during these responses. Histological, immunohistochemical, in situ hybridization, and trafficking studies have been carried out ot evaluate splenic distribution of lymphocyte subsets and cytokine producing cells after in vivo induciton of IFN. The experiments presented here will expand characterization of in vivo responses to examine expression and function of tumor necrosis factor-alpha (TNF-alpha) and interleukin-12 (IL- 12), as well as to evaluate immunoregulatory roles that activated NK cells may play by producing and delivering IFN-gamma, TNF-alpha, and/or granulocyte/macrophage colony stimulating factor (GM-CSF). The main hypotheses are: that, in addition to eliciting NK cell activation and blastogenesis, early, virus-induced production of cytokines precipitates a cascade reaction ultimately resulting in a protective T cell response, that NK cells are important intermediaries in this cascade, and that activated T cells contribute to regulation of NK cell responses by competing with NK cells for available growth factors. These will be examined by asking the following. 1) Are NK cells delivering cytokines to splenic marginal zones and antigen presenting cells located at those sites? 2) What is the role of NK cells and/or NK cell-derived cytokines for induciton of CD8+/CTL responses to viral infections? 3) What induces NK cell blastogenesis and/or development of NK cells from bone marrow precursor cells? 4) Is there a requirement for IL-2 to support extended NK cell responses in the absence of CD8+ T cells? 5) Are there in vivo conditions where CD3epsilon chain expression is induced in NK cells? Immunological, molecular, histological, and cell trafficking studies will be used to answer these questions. The experiments will take advantage of genetically altered mice which we have identified as being NK cell response-enhanced. In addition, they will use exciting new mouse lines, transgenic for the human CD3epsilon gene, which we have characterized as NK cell deficient. These mice are extraordinary as they are the first mice negative for both NK cell functions and cell numbers. The information resulting from this work will generate basic immunological knowledge as well as significant new information for developing anti-viral and/or anti-cancer treatment protocols.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Immunological Sciences Study Section (IMS)
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Finerty, John F
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Brown University
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Biron, Christine A; Tarrio, Margarite L (2015) Immunoregulatory cytokine networks: 60 years of learning from murine cytomegalovirus. Med Microbiol Immunol 204:345-54
Donnelly, Raymond P; Loftus, Róisín M; Keating, Sinéad E et al. (2014) mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J Immunol 193:4477-84
Tarrio, Margarite L; Lee, Seung-Hwan; Fragoso, Maria F et al. (2014) Proliferation conditions promote intrinsic changes in NK cells for an IL-10 response. J Immunol 193:354-63
Kallal, Lara E; Biron, Christine A (2013) Changing partners at the dance: Variations in STAT concentrations for shaping cytokine function and immune responses to viral infections. JAKSTAT 2:e23504
Lee, Seung-Hwan; Fragoso, Maria F; Biron, Christine A (2012) Cutting edge: a novel mechanism bridging innate and adaptive immunity: IL-12 induction of CD25 to form high-affinity IL-2 receptors on NK cells. J Immunol 189:2712-6
Vidal, Silvia M; Khakoo, Salim I; Biron, Christine A (2011) Natural killer cell responses during viral infections: flexibility and conditioning of innate immunity by experience. Curr Opin Virol 1:497-512
Mack, Ethan A; Kallal, Lara E; Demers, Delia A et al. (2011) Type 1 interferon induction of natural killer cell gamma interferon production for defense during lymphocytic choriomeningitis virus infection. MBio 2:
Miyagi, Takuya; Lee, Seung-Hwan; Biron, Christine A (2010) Intracellular staining for analysis of the expression and phosphorylation of signal transducers and activators of transcription (STATs) in NK cells. Methods Mol Biol 612:159-75
Biron, Christine A (2010) Expansion, maintenance, and memory in NK and T cells during viral infections: responding to pressures for defense and regulation. PLoS Pathog 6:e1000816
Lee, Seung-Hwan; Biron, Christine A (2010) Here today--not gone tomorrow: roles for activating receptors in sustaining NK cells during viral infections. Eur J Immunol 40:923-32

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