Peripheral T cell tolerance is an important immunological outcome that inhibits deleterious immune responses to both self and non-self antigens (Ags). Impaired immune tolerance can manifest as either allergic or autoimmune disease. In a murine model of tolerance induced by inhaled Ag, we previously identified regulatory T cells (Tregs) expressing Foxp3 and membrane-bound TGF-? (mTGF-?) that functionally suppressed allergic airway inflammation induced by the Ag. We also demonstrated cross-talk between mTGF-? and Notch1 as one mechanism of induced tolerance. With the current concepts of adaptive/induced Tregs (iTregs) and infectious tolerance elicited in response to foreign Ags, we have initiated studies to examine generation of iTregs with a bigger goal of understanding how the function of a Treg can be enhanced and stabilized. Using Foxp3 reporter mice in conjunction with CD11c-DTR mice that express the diphtheria toxin receptor on CD11c cells, we have established a system to determine which dendritic cell (DC) subsets contribute to iTreg induction. In other studies of involvement of Tregs in controlling allergic disease, we have found a role for vitamin D3 in promoting mTGF-? cells in the context of allergic bronchopulmonary aspergillosis (ABPA). Given the current interest in vit D3 in regulating allergic diseases with little understanding of how vit D receptor (VDR)-mediated effects cause immunosuppression, we propose to use genetically altered mice to investigate the role of vit D in Foxp3- versus CD11c-expressing cells in iTreg generation. Finally, as proposed in the previous cycle of this grant, we have successfully generated a CD4 T cell-specific inducible transgenic mouse expressing Hes1, a downstream target of Notch1. This mouse was generated to understand the role of Hes1 in Treg-mediated immunosuppression, particularly in the context of inflammation, which compromises Treg function. Our overall hypothesis for this proposal is: Treg induction by inhaled Ag involves a subset of DCs and the process can be enhanced and stabilized by VDR- and Notch1/Hes1 pathways. To address this hypothesis we will:
Aim I. Identify the specific DC subsets in the lung that induce iTregs in response to Ag.
Aim II. Investigate the involvement of vitamin D and VDR in Foxp3+ Tregs versus CD11c+ cells in promoting inhaled tolerance.
Aim III. Study the ability of Hes1, a downstream target of Notch1, expressed in an inducible fashion in CD4+ T cells, to stabilize and preserve Treg function in the lungs of mice subjected to airway inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048927-15
Application #
8622182
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Minnicozzi, Michael
Project Start
2011-03-15
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2014
Total Cost
$375,708
Indirect Cost
$127,716
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Khare, Anupriya; Raundhal, Mahesh; Chakraborty, Krishnendu et al. (2016) Mitochondrial H2O2 in Lung Antigen-Presenting Cells Blocks NF-κB Activation to Prevent Unwarranted Immune Activation. Cell Rep 15:1700-14
Ray, Anuradha; Raundhal, Mahesh; Oriss, Timothy B et al. (2016) Current concepts of severe asthma. J Clin Invest 126:2394-403
Gauthier, Marc; Ray, Anuradha; Wenzel, Sally E (2015) Evolving Concepts of Asthma. Am J Respir Crit Care Med 192:660-8
Khare, Anupriya; Chakraborty, Krishnendu; Raundhal, Mahesh et al. (2015) Cutting Edge: Dual Function of PPARγ in CD11c+ Cells Ensures Immune Tolerance in the Airways. J Immunol 195:431-5
Raundhal, Mahesh; Morse, Christina; Khare, Anupriya et al. (2015) High IFN-γ and low SLPI mark severe asthma in mice and humans. J Clin Invest 125:3037-50
Ray, Anuradha; Oriss, Timothy B; Wenzel, Sally E (2015) Emerging molecular phenotypes of asthma. Am J Physiol Lung Cell Mol Physiol 308:L130-40
Oczypok, Elizabeth A; Milutinovic, Pavle S; Alcorn, John F et al. (2015) Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells. J Allergy Clin Immunol 136:747-756.e4
Oriss, Timothy B; Krishnamoorthy, Nandini; Raundhal, Mahesh et al. (2014) Cutting Edge: MMP-9 inhibits IL-23p19 expression in dendritic cells by targeting membrane stem cell factor affecting lung IL-17 response. J Immunol 192:5471-5
Oriss, Timothy B; Krishnamoorthy, Nandini; Ray, Prabir et al. (2014) Dendritic cell c-kit signaling and adaptive immunity: implications for the upper airways. Curr Opin Allergy Clin Immunol 14:7-12
Poe, S L; Arora, M; Oriss, T B et al. (2013) STAT1-regulated lung MDSC-like cells produce IL-10 and efferocytose apoptotic neutrophils with relevance in resolution of bacterial pneumonia. Mucosal Immunol 6:189-99

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