The goal of this proposal is to understand the mechanisms regulating mouse natural killer (NK) cell proliferation. By the techniques of centrifugal elutriation, sensitivity to a drug specific for dividing cells, and a single-cell cytotoxicity assay which detects lysis mediated by blast-NK cells, I have shown: 1) that interferon (IFN) and IFN inducers stimulate blastogenesis of NK cells in vivo; 2) that the primary lymphoid organ for this blastogenesis is the spleen; and 3) that this blastogenesis is accompanied by increases in turnover rates and numbers of NK cells. I recently have developed an in vitro system to support the proliferation of blast-NK cells elicited by IFN in vivo. The precursors of cells expanding, in this culture system, to mediate lysis of NK sensitive target cells are isolated in equal frequencies from both euthymic and athymic mice. This appears, therefore, to be an excellent model for the characterization of NK cell proliferation. The in vivo and in vitro systems will be combined to study NK cell expansion, the mechanisms of induction and the regulation of NK cell proliferation. Blastogenesis of NK cells will be induced in vivo by stimulation with poly I:C or with purified IFN's ( or ). Further expansion of NK cells will be carried out by multiple stimulations with IFN in vivo and by outgrowth of blast-NK cells in culture. A role for the T cell growth factor, interleukin-2 (IL-2), in the proliferation of NK cells will be determined by quantitating the expression of IL-2 receptors on in vivo elicited blast-NK cells and by growing these blast-NK cells in cloned IL-2. NK cell proliferation in the context of T cell responses will be examined during the infection of euthymic mice with lymphocytic choriomeningitis virus. The information obtained from these studies will be used to expand NK cells and induce antitumor and antiviral states in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA041268-04
Application #
3181584
Study Section
Immunobiology Study Section (IMB)
Project Start
1987-12-01
Project End
1993-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Brown University
Department
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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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