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Ifnβ Reprograms Th2 Promoting Mature Lung TNFR2+ cDC2 Subset in vivo to Generate Regulatory T Cells and Restore Lung Mucosal Tolerance

36 Pages Posted: 22 May 2019 Sneak Peek Status: Under Review

See all articles by Samira Mansouri

Samira Mansouri

University of Florida, College of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine

Divya s. Katikaneni

University of Florida, College of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine

Himanshu Gogoi

University of Florida, College of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine

mauricio pipkin

University of Florida, College of Medicine, Department of Surgery, Division of Thoracic and Cardiovascular Surgery

Tiago N. Machuca

University of Florida, College of Medicine, Department of Surgery, Division of Thoracic and Cardiovascular Surgery

Amir M. Emtiazjoo

University of Florida, College of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine

Lei Jin

University of Florida, College of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine

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Abstract

Lung dendritic cells and regulatory T cells control lung mucosal tolerance. Here, we identified a lung-resident IDO-1+TNFR2+ conventional DC2 (iR2D2) subset that induces antigen-specific regulatory T cells in the lung. iR2D2 is a microenvironment specialized DC subset whose existence depends on its constitutive TNFR2-pRelB-IDO-1 signaling. The iR2D2 intrinsic IFNAR-TGFβ1 signaling is necessary and sufficient for regulatory T cells induction in vivo. Surprisingly, iR2D2 is plastic. In a house dust mite (HDM) model of asthma, iR2D2 generates lung Th2 responses. Remarkably, intranasally administration of IFNβ reprogramed HDM-induced Th2-promoting iR2D2 back to generate regulatory T cells, reversed lung inflammation and protected mice from subsequent asthma exacerbation. Healthy human lung has a phenotypically similar tolerogenic iR2D2, which became IL-4+ in emphysema patients. Finally, IFNβ successfully reprogramed human emphysema iR2D2 ex vivo. These findings elucidate a fundamental mechanism controlling lung tolerance and a strategy to restore lung tolerance in inflammatory lung diseases.

Keywords: lung mucosal tolerance, TNFR2, IDO-1, dendritic cells subset, regulatory T cells, asthma

Suggested Citation

Mansouri, Samira and Katikaneni, Divya s. and Gogoi, Himanshu and pipkin, mauricio and Machuca, Tiago N. and Emtiazjoo, Amir M. and Jin, Lei, Ifnβ Reprograms Th2 Promoting Mature Lung TNFR2+ cDC2 Subset in vivo to Generate Regulatory T Cells and Restore Lung Mucosal Tolerance (May 20, 2019). IMMUNITY-D-19-00513. Available at SSRN: https://ssrn.com/abstract=3391469 or http://dx.doi.org/10.2139/ssrn.3391469
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Samira Mansouri

University of Florida, College of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine ( email )

Gainesville, FL
United States

Divya s. Katikaneni

University of Florida, College of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine ( email )

Gainesville, FL
United States

Himanshu Gogoi

University of Florida, College of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine ( email )

Gainesville, FL
United States

Mauricio Pipkin

University of Florida, College of Medicine, Department of Surgery, Division of Thoracic and Cardiovascular Surgery ( email )

Gainesville, FL
United States

Tiago N. Machuca

University of Florida, College of Medicine, Department of Surgery, Division of Thoracic and Cardiovascular Surgery

Gainesville, FL
United States

Amir M. Emtiazjoo

University of Florida, College of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine ( email )

Gainesville, FL
United States

Lei Jin (Contact Author)

University of Florida, College of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine ( email )

Gainesville, FL
United States

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