The host response to antigenic challenge requires initiation, effector, and resolution phases of inflammation.? Just as positive signals are required to initiate immune responses, the resolution of inflammation is also an? active process that depends upon signaling through inhibitory receptors. These signals are provided to T? cells by activating or inhibitory members of the B7:CD28 receptor family. Atopic asthma is a T cell mediated? immune response characterized by T helper 2 type inflammation in the airway. Using a murine model of this? disease we have shown that costimulation through CD28 is important in the initiation and maintenance of? inflammation. We now find that inhibitory receptor function is equally critical in the regulation of airway? inflammation. We demonstrate that there is temporally regulated induction of both PD-1 and BTLA and their? ligands in lung cells following allergen challenge. Furthermore, mice deficient in these receptors demonstrate? prolonged airway inflammation following a single allergen challenge. Therefore, we hypothesize that the? regulated expression of BTLA and PD-1 on lymphocytes and their ligands HVEM, PDL1 and/or PDL2? parenchyma! or infiltrating immune cells limit the development of chronic airway inflammation. In? Specific Aim 1 we will focus on the regulation of ligand expression. We will determine specifically which cell? types in the lung express each ligand and what factors regulate their expression. Using an inducible? transgenic mouse system we will determine if overexpression of the ligand in vivo can either prevent the? onset of lung inflammation, or terminate an ongoing inflammatory response. In addition, we will use primary? cultured murine tracheal epithelial cells to dissect the elements that regulate expression in airway cells. In? Specific Aim 2 we turn our focus to the T cell. Our preliminary data establishes that in the absence of PD-1? or BTLA there is prolonged inflammation following a single allergen challenge. We will extend this? observation to determine the role of these receptors in models of chronic allergen exposure. Furthermore,? we will determine the contributions of cell recruitment, proliferation and or survival in the accumulation of? lymphocytes in the lung.
While aims 1 and 2 we use an experimental murine model, in aim 3 we will begin? an analysis of these receptorligand interactions in humans. We will compare the expression and function of? both PD-1 and BTLA in normal and asthmatic subjects. Within the context of this collaborative program we? will interact extensively with Project 1 in our studies of epithelial cells. In project 2, the focus is on regulatory? T cells, which may utilize inhibitory receptors such as PD-1 and BTLA to regulate T cell function. Thus, the? synergistic interactions of the group will undoubtedly strengthen the overall group. We believe the? combination of expertise and reagents available in this program leave us uniquely poised to delineate how? PD-1 and BTLA limit lung inflammation. Studies such as these may provide the basis for the development of? novel immunotherapeutic approaches to chronic inflammatory lung diseases such as asthma.

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)
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Washington University
Saint Louis
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Keeler, Shamus P; Agapov, Eugene V; Hinojosa, Michael E et al. (2018) Influenza A Virus Infection Causes Chronic Lung Disease Linked to Sites of Active Viral RNA Remnants. J Immunol 201:2354-2368
Myung, Jihwan; Schmal, Christoph; Hong, Sungho et al. (2018) The choroid plexus is an important circadian clock component. Nat Commun 9:1062
Li, Shuai; O'Neill, Sofia R S; Zhang, Yong et al. (2017) Estrogen receptor ? is required for oviductal transport of embryos. FASEB J 31:1595-1607
Benedetto, Roberta; Ousingsawat, Jiraporn; Wanitchakool, Podchanart et al. (2017) Epithelial Chloride Transport by CFTR Requires TMEM16A. Sci Rep 7:12397
Liu, Yongjian; Gunsten, Sean P; Sultan, Deborah H et al. (2017) PET-based Imaging of Chemokine Receptor 2 in Experimental and Disease-related Lung Inflammation. Radiology 283:758-768
Steed, Ashley L; Christophi, George P; Kaiko, Gerard E et al. (2017) The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science 357:498-502
Woodruff, Prescott G; van den Berge, Maarten; Boucher, Richard C et al. (2017) American Thoracic Society/National Heart, Lung, and Blood Institute Asthma-Chronic Obstructive Pulmonary Disease Overlap Workshop Report. Am J Respir Crit Care Med 196:375-381
Chatterjee, Srirupa; Luthra, Priya; Esaulova, Ekaterina et al. (2017) Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses. Nat Microbiol 2:17101
Zhou, Weisong; Toki, Shinji; Zhang, Jian et al. (2016) Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses. Am J Respir Crit Care Med 193:31-42
Banathy, Alex; Cheung-Flynn, Joyce; Goleniewska, Kasia et al. (2016) Heat Shock-Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of ?2-Adrenergic Receptor. Am J Respir Cell Mol Biol 55:225-33

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