This is the first renewal application for this Program Project Grant, currently at 3.5 years of a 4 year grant. The focus has been and remains a study of the molecular and cellular pathways that regulate the balance of Th1 and Th2 cytokine patterns. It makes a particular effort to integrate specific signal pathways with important cellular questions. These studies make use of several in vivo models of infectious and autoimmune diseases as well as immune memory. It also examines an aspect of Th1/Th2 regulation that is less frequently considered, the cellular interactions that influence the Th1/Th2 balance once it is established; in this case by gamma/delta T cells. This Program Project also combines the expertise of two institutions, The University of Vermont (UVM) and the Trudeau Institute, two hours from UVM in Saranac Lake, NY. The UVM investigators (Drs. Ralph Budd, Mercedes Rincon, Sally Huber, Cory Teuscher) have expertise is cell signaling, immunogenetics, and viral immunology, whereas the Trudeau investigators (Drs. Susan Swain, Laura Haynes, and Markus Mohrs) have expertise in the study of immune memory and cytokine gene regulation, both of which are critical to our studies. The principal signal pathways studied in this Program Project converge on two important transcription factors for cytokine gene regulation, NFAT and NF-kB. IL-6 triggers IL-4 production in naive CD4+ -T cells via NFATc2 (Project 1), whereas gamma/delta T cells express high levels of FasL via NFAT which selectively kill Th2 cells in a Fas-dependent manner (Project 3). Similarly, c-FLIP (the death receptor inhibitor studied in Project 2) and the Histamine 1 Receptor (H1R, a susceptibility gene locus for EAE studied in Project 4) converge on the NF-kB pathway, c-FLIP signals NF-kappaB via RIP to costimulate T cells, and H1R connects to G-proteins and PKC theta to signal NF-kappaB. All four projects examine how these signal pathways and cell types influence the Th1/Th2 environment. In addition, Projects 1 and 2 also examine how the c-FLIP/NF-kappaB and IL-6/NFAT pathways influence the transition from effector Th1/Th2 to memory CD4+ T cell. Progress during the current funding period has been substantial (over 30 publications), 8 of which are multi-authored among the Program investigators, the renewal application includes two new investigators, Dr. Cory Teuscher, a leading immunogeneticist, and Dr. Markus Mohrs, with expertise in cytokine gene regulation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-CL-I (S1))
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Deckhut Augustine, Alison M
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University of Vermont & St Agric College
Internal Medicine/Medicine
Schools of Medicine
United States
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Collins, Cheryl C; Bashant, Kathleen; Erikson, Cuixia et al. (2016) Necroptosis of Dendritic Cells Promotes Activation of ?? T Cells. J Innate Immun 8:479-92
Saligrama, P T; Fortner, K A; Secinaro, M A et al. (2014) IL-15 maintains T-cell survival via S-nitrosylation-mediated inhibition of caspase-3. Cell Death Differ 21:904-14
Koenig, Andreas; Buskiewicz, Iwona A; Fortner, Karen A et al. (2014) The c-FLIPL cleavage product p43FLIP promotes activation of extracellular signal-regulated kinase (ERK), nuclear factor ?B (NF-?B), and caspase-8 and T cell survival. J Biol Chem 289:1183-91
Buskiewicz, Iwona A; Koenig, Andreas; Roberts, Brian et al. (2014) c-FLIP-Short reduces type I interferon production and increases viremia with coxsackievirus B3. PLoS One 9:e96156
Roberts, Brian J; Moussawi, Mohamad; Huber, Sally A (2013) Sex differences in TLR2 and TLR4 expression and their effect on coxsackievirus-induced autoimmune myocarditis. Exp Mol Pathol 94:58-64
Case, Laure K; Wall, Emma H; Dragon, Julie A et al. (2013) The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease. Genome Res 23:1474-85
Koenig, Andreas; Fortner, Karen A; King, Benjamin R et al. (2012) Proliferating ?? T cells manifest high and spatially confined caspase-3 activity. Immunology 135:276-86
Liu, Wei; Dienz, Oliver; Roberts, Brian et al. (2012) IL-21R expression on CD8+ T cells promotes CD8+ T cell activation in coxsackievirus B3 induced myocarditis. Exp Mol Pathol 92:327-33
Rincon, Mercedes; Irvin, Charles G (2012) Role of IL-6 in asthma and other inflammatory pulmonary diseases. Int J Biol Sci 8:1281-90
Rincon, Mercedes R; Oppenheimer, Karen; Bonney, Elizabeth A (2012) Selective accumulation of Th2-skewing immature erythroid cells in developing neonatal mouse spleen. Int J Biol Sci 8:719-30

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