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.

Public Health Relevance

The goal of this application is to understand how regulatory T cells are induced in the lung in response to allergens and how their suppressive function can be enhanced and stabilized.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Minnicozzi, Michael
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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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
Ray, Anuradha; Chakraborty, Krishnendu; Ray, Prabir (2013) Immunosuppressive MDSCs induced by TLR signaling during infection and role in resolution of inflammation. Front Cell Infect Microbiol 3:52
Khare, Anupriya; Krishnamoorthy, Nandini; Oriss, Timothy B et al. (2013) Cutting edge: inhaled antigen upregulates retinaldehyde dehydrogenase in lung CD103+ but not plasmacytoid dendritic cells to induce Foxp3 de novo in CD4+ T cells and promote airway tolerance. J Immunol 191:25-9
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
Arora, Meenakshi; Poe, Stephanie L; Ray, Anuradha et al. (2011) LPS-induced CD11b+Gr1(int)F4/80+ regulatory myeloid cells suppress allergen-induced airway inflammation. Int Immunopharmacol 11:827-32
Ray, Prabir; Arora, Meenakshi; Poe, Stephanie L et al. (2011) Lung myeloid-derived suppressor cells and regulation of inflammation. Immunol Res 50:153-8
Fei, Mingjian; Bhatia, Shikha; Oriss, Timothy B et al. (2011) TNF-alpha from inflammatory dendritic cells (DCs) regulates lung IL-17A/IL-5 levels and neutrophilia versus eosinophilia during persistent fungal infection. Proc Natl Acad Sci U S A 108:5360-5
Bhatia, Shikha; Fei, Mingjian; Yarlagadda, Manohar et al. (2011) Rapid host defense against Aspergillus fumigatus involves alveolar macrophages with a predominance of alternatively activated phenotype. PLoS One 6:e15943
Ray, Prabir; Krishnamoorthy, Nandini; Oriss, Timothy B et al. (2010) Signaling of c-kit in dendritic cells influences adaptive immunity. Ann N Y Acad Sci 1183:104-22

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