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.
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.
|Oriss, Timothy B; Raundhal, Mahesh; Morse, Christina et al. (2017) IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice. JCI Insight 2:|
|Das, Sudipta; Raundhal, Mahesh; Chen, Jie et al. (2017) Respiratory syncytial virus infection of newborn CX3CR1-deficent mice induces a pathogenic pulmonary innate immune response. JCI Insight 2:|
|Gauthier, Marc; Chakraborty, Krishnendu; Oriss, Timothy B et al. (2017) Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias. JCI Insight 2:|
|Chakraborty, Krishnendu; Raundhal, Mahesh; Chen, Bill B et al. (2017) The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia. Nat Commun 8:13944|
|Ray, Anuradha; Raundhal, Mahesh; Oriss, Timothy B et al. (2016) Current concepts of severe asthma. J Clin Invest 126:2394-403|
|Khare, Anupriya; Raundhal, Mahesh; Chakraborty, Krishnendu et al. (2016) Mitochondrial H2O2 in Lung Antigen-Presenting Cells Blocks NF-?B Activation to Prevent Unwarranted Immune Activation. Cell Rep 15:1700-14|
|Raundhal, Mahesh; Morse, Christina; Khare, Anupriya et al. (2015) High IFN-? and low SLPI mark severe asthma in mice and humans. J Clin Invest 125:3037-50|
|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|
|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 PPAR? in CD11c+ Cells Ensures Immune Tolerance in the Airways. J Immunol 195:431-5|
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