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Sci Transl Med. 2018 Sep 26;10(460). pii: eaar8356. doi: 10.1126/scitranslmed.aar8356.

PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production.

Author information

1
Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. wonder.drake@vanderbilt.edu lindsay.j.celada@vanderbilt.edu.
2
Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
3
Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
4
Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
5
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
6
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
7
Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45219, USA.
8
Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
9
Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
10
Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA.
11
National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton Hospital, London SW7 2AZ, UK.
12
Fibrosis Research Group, National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK.
13
Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL 60637, USA.
14
Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, University of Western Australia, Nedlands, Western Australia 6009, Australia.
15
Institute for Respiratory Health, Centre for Respiratory Health, School of Biomedical Sciences, University of Western Australia, Nedlands, Western Australia 6009, Australia.

Abstract

Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1+CD4+ T cells with reduced proliferative capacity and increased transforming growth factor-β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4+ T cells. PD-1+ T helper 17 cells are the predominant CD4+ T cell subset expressing TGF-β. Coculture of PD-1+CD4+ T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4+ T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1+CD4+ T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.

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