This U19 application for a Multi-Investigator Program to examine Immune Mechanisms of Virus Control focuses on the role of CD8 + effector T-cells in orchestrating clearance of virus and in the control of tissue inflammation and injury associated with the host response to virus infection. Four highly interactive and synergistic Projects and two supporting scientific cores comprise program. These projects are designed to explore the role of innate immune cells (notably natural killer (NK) cells and dendritic cell/macrophages) and their products in regulating the development of effector CD8 + T cells which can efficiently eliminates virus/virus infected cells and control excess and potentially injurious inflammation associated with T cell recognition of viruses at different sites of infection.
The Specific Aims of the Program fulfill several of the stated Aims of the RFA including understanding and defining the role of innate immune cells in regulating adaptive responses at different sites of virus infection.'This Program also deals with a topic as important as effective virus clearance that is the control of tissue inflammation and injury and explores the contribution of intrinsic mechanisms of control of tissue inflammation and injury exhibited by effector CD8 + T cells (i.e. effector T cell derived I L-10 and inhibitory NK receptor expression by the effector T cells). The Program brings together project leaders with unique expertise and diverse and complementary skills in the areas of Viral Immunology, Mammalian Genetics, Virology and Clinical Medicine. The individual Project Leaders and Core Directors have both prior and ongoing collaborations. In this program we proposed to examine the following questions: How does I L-10 (interleukin-10) produced by antiviral CD8 + effector T-cells affect virus clearance and control lung inflammation in acute respiratory virus infection and what factors control the production of this regulatory cytokine by effector T-cells (Project 1)?;2. What is the nature of the defect in the CD8 + T-cell effector response to hepatotropic virus infection and adaptive immune induction in the liver and how do liver NK cells (and liver dendritic cell-NK cell interactions) regulate the magnitude and the quality of the CD8 + T cell response (Project 2)7;3. How does NK cell mediated control of early virus replication at the site of infection in a secondary lymphoid organ i.e. the spleen, and the activation state of the NK cells, affect virus elimination and the tempo and quality of the antiviral CD8 + T cell response (Project 3)?;4. What are the factors that control the expression of an inhibitory NK-type receptor NKG2A on CD8 + effector T cells and how does that engagement of this inhibitory receptor control excess Inflammation and inhibit immune pathology in the virus infected lungs (Project 4)? PROJECT 1: lnterleukin-10 in acute respiratory virus infection (Braciale, T) PROJECT 1 DESCRIPTION (provided by applicant): Pulmonary inflammation and injury is a frequent (and, in some instances, lethal) outcome of virus infections of the respiratory tract. Respiratory virus infection triggers a coordinated response from the host innate and adaptive immune systems. The host response is essential for virus clearance and recovery, but is also a significant cause of pulmonary injury that can accompany virus elimination. Relevant recent examples of this are the immune-mediated lung inflammation/injury observed in human infections with the SARS coronavirus and the H5N1 avian influenza viruses. The long-term goal of Project 1 is to define and characterize the interactions between cells of the innate immune system i.e. dendritic cells, monocyte/ macrophage, NK cells and adaptive immune effector T lymphocytes (Te) in the process of virus clearance and in the control of inflammation/injury during experimental virus infection of the respiratory tract. The foundation for this application is our recent and unexpected findings in the murine model of type A influenza infection that anti-viral effector T-cells (both CD4 +Te and more prominently CD8 +Te) infiltrating the infected lungs produce high levels of the anti-inflammatory/regulatory cytokines IL-10 during the Te response to infection and virus elimination. Furthermore, we found that blocking the effect of Te-derived IL- 10 during infection results in increased pulmonary inflammation and lethal injury. Our evidence further suggests that this Te-derived IL-10 plays a central role in controlling the level of lung inflammation/injury produced by mononuclear cells infiltrating the infected lungs in response to virus infection and the proinflammatory mediators released by virus- immune (Te). We wish to analyze the expression and regulation of IL-10 and specifically Te-derived IL-10 in the infected lungs and the impact of this cytokine on the control of virus clearance and lung inflammation/injury.
The aims of Project 1 are: 1. To evaluate the cellular sources and effects of IL-10 on influenza virus infection;2. To analyze the regulation of IL-10 production by Te during influenza infection;3. To determine the impact of viral infection on the production of Te-derived IL- 10. The proposed studies are designed to complement ongoing related studies in Projects 2, 3 and 4.

Public Health Relevance

We know from research carried out over several decades that to effectively cure or prevent the virus infection it is necessary for the immune system to eliminate the virus from the body. However, the immune system must do this without itself causing excess inflammation damage to body tissues and organs at the site of infection. The Projects that make up this Program will in concert provide us with new information on how these two facets of virus infection and the host response, that is, elimination of the virus and immune mediated injury can be balanced.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BDP-I (J3))
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Miller, Lara R
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University of Virginia
Schools of Medicine
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Dolina, Joseph S; Braciale, Thomas J; Hahn, Young S (2014) Liver-primed CD8+ T cells suppress antiviral adaptive immunity through galectin-9-independent T-cell immunoglobulin and mucin 3 engagement of high-mobility group box 1 in mice. Hepatology 59:1351-65
Moser, Emily K; Hufford, Matthew M; Braciale, Thomas J (2014) Late engagement of CD86 after influenza virus clearance promotes recovery in a FoxP3+ regulatory T cell dependent manner. PLoS Pathog 10:e1004315
Ely, Kenneth H; Matsuoka, Mitsuo; DeBerge, Matthew P et al. (2014) Tissue-protective effects of NKG2A in immune-mediated clearance of virus infection. PLoS One 9:e108385
DeBerge, Matthew P; Ely, Kenneth H; Enelow, Richard I (2014) Soluble, but not transmembrane, TNF-? is required during influenza infection to limit the magnitude of immune responses and the extent of immunopathology. J Immunol 192:5839-51
Kim, Taeg S; Gorski, Stacey A; Hahn, Steven et al. (2014) Distinct dendritic cell subsets dictate the fate decision between effector and memory CD8(+) T cell differentiation by a CD24-dependent mechanism. Immunity 40:400-13
Yoo, Jae-Kwang; Braciale, Thomas J (2014) IL-21 promotes late activator APC-mediated T follicular helper cell differentiation in experimental pulmonary virus infection. PLoS One 9:e105872
Yoo, Jae-Kwang; Kim, Taeg S; Hufford, Matthew M et al. (2013) Viral infection of the lung: host response and sequelae. J Allergy Clin Immunol 132:1263-76; quiz 1277
Braciale, Thomas J; Hahn, Young S (2013) Immunity to viruses. Immunol Rev 255:5-12
Gorski, Stacey Ann; Hahn, Young S; Braciale, Thomas J (2013) Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection. PLoS Pathog 9:e1003615
Goh, Celeste; Narayanan, Sowmya; Hahn, Young S (2013) Myeloid-derived suppressor cells: the dark knight or the joker in viral infections? Immunol Rev 255:210-21

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