In susceptible individuals, asthma is a complex disease characterized by heightened responses to relatively innocuous antigens encountered via the respiratory tract. In a shift in thinking away from simple imbalances in Th2 and Th1 responses, there is increasing evidence for a protective role for regulatory T cells in allergic disease where they exhibit control over effector Th1 and Th2 cells. Naturally-occurring CD4+CD25+Foxp3+ regulatory cells (nTregs) isolated from the lungs of naive mice and transferred intratracheally into sensitized recipients prior to challenge suppress all aspects of lung allergic responses including airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine production, and goblet cell metaplasia. Conversely, depletion of these cells with anti-CD25 enhanced all of these responses. Our data indicate that the suppressive phenotype of nTregs is dependent on CD8- MHC I interactions and their production of IL-10 and TGF2. In the absence of CD8-MHC I interactions, the phenotype of the nTregs converts to one which enhances the development of lung allergic responses, and is associated with increased IL-13 production and decreased Foxp3 expression. By contrast, signaling through the glucocorticoid inducible tumor necrosis factor receptor (GITR) attenuates the suppressive phenotype. We will define the role of these nTregs in regulating mast cell-dependent and -independent AHR and whether they are responsible for the tolerant state induced by repeated allergen challenge. Using biochemical tools, genetic manipulation and in vitro and in vivo approaches, we will define the underlying mechanisms whereby CD8-MHC I interactions signal and maintain Foxp3 expression and the suppressive phenotype, and determine how signaling through GITR-GITR-ligand attenuates suppression, subverting and converting nTregs to an enhancing phenotype, characterized by Th2 cytokine production. In these approaches, we will delineate the counter-regulatory signals provided through Foxp3 and GITR and the interplay between these two defining events that appear to govern the fate (suppressive or enhancing phenotype) of nTregs. For the first time, these studies will identify the indispensable role and mechanism whereby Foxp3+nTregs control the development of lung allergic responses in sensitized hosts exposed to allergen challenge. Elucidation of the molecular basis for the functional activation of nTregs and the underlying mechanisms dictating nTreg-mediated suppression or nTreg conversion to an enhancing phenotype will form the basis for the control of their function in diseases such as asthma.

Public Health Relevance

Asthma now afflicts more than 30 million Americans and despite the introduction of new therapies, morbidity and mortality continue to increase. If we are to impact this disease, a greater understanding of the mechanisms underlying asthma progression, delineation of the regulatory pathways, and identification of new strategies are required. This proposal addresses novel pathways that may regulate airway hyperresponsiveness and inflammation, with the potential of revealing novel and important therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077609-05
Application #
8503580
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Davidson, Wendy F
Project Start
2009-08-15
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$451,091
Indirect Cost
$161,930
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
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Gelfand, Erwin W (2017) Importance of the leukotriene B4-BLT1 and LTB4-BLT2 pathways in asthma. Semin Immunol 33:44-51
Joetham, Anthony; Schedel, Michaela; O'Connor, Brian P et al. (2017) Inducible and naturally occurring regulatory T cells enhance lung allergic responses through divergent transcriptional pathways. J Allergy Clin Immunol 139:1331-1342
Wang, Meiqin; Yang, Ivana V; Davidson, Elizabeth J et al. (2017) Forkhead box protein 3 demethylation is associated with tolerance induction in peanut-induced intestinal allergy. J Allergy Clin Immunol :
Wang, M; Han, J; Domenico, J et al. (2016) Combined blockade of the histamine H1 and H4 receptor suppresses peanut-induced intestinal anaphylaxis by regulating dendritic cell function. Allergy 71:1561-1574
Schedel, Michaela; Jia, Yi; Michel, Sven et al. (2016) 1,25D3 prevents CD8(+)Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter. Nat Commun 7:10213
Takeda, Katsuyuki; Shiraishi, Yoshiki; Ashino, Shigeru et al. (2015) Eosinophils contribute to the resolution of lung-allergic responses following repeated allergen challenge. J Allergy Clin Immunol 135:451-60
Chung, Eun Hee; Jia, Yi; Ohnishi, Hiroshi et al. (2014) Leukotriene B4 receptor 1 is differentially expressed on peripheral T cells of steroid-sensitive and -resistant asthmatics. Ann Allergy Asthma Immunol 112:211-216.e1
Han, Junyan; Takeda, Katsuyuki; Wang, Meiqin et al. (2014) Effects of anti-g and anti-f antibodies on airway function after respiratory syncytial virus infection. Am J Respir Cell Mol Biol 51:143-54
Wang, Meiqin; Gelfand, Erwin W (2014) Targeting Pim1 kinase in the treatment of peanut allergy. Expert Opin Ther Targets 18:177-83

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