BibTex format
@article{Celada:2018:10.1126/scitranslmed.aar8356,
author = {Celada, LJ and Kropski, JA and Herazo-Maya, JD and Luo, W and Creecy, A and Abad, AT and Chioma, OS and Lee, G and Hassell, NE and Shaginurova, GI and Wang, Y and Johnson, JE and Kerrigan, A and Mason, WR and Baughman, RP and Ayers, GD and Bernard, GR and Culver, DA and Montgomery, CG and Maher, TM and Molyneaux, PL and Noth, I and Mutsaers, SE and Prele, CM and Peebles, RS and Newcomb, DC and Kaminski, N and Blackwell, TS and Van, Kaer L and Drake, WP},
doi = {10.1126/scitranslmed.aar8356},
journal = {Science Translational Medicine},
title = {PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production},
url = {http://dx.doi.org/10.1126/scitranslmed.aar8356},
volume = {10},
year = {2018}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - 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.
AU - Celada,LJ
AU - Kropski,JA
AU - Herazo-Maya,JD
AU - Luo,W
AU - Creecy,A
AU - Abad,AT
AU - Chioma,OS
AU - Lee,G
AU - Hassell,NE
AU - Shaginurova,GI
AU - Wang,Y
AU - Johnson,JE
AU - Kerrigan,A
AU - Mason,WR
AU - Baughman,RP
AU - Ayers,GD
AU - Bernard,GR
AU - Culver,DA
AU - Montgomery,CG
AU - Maher,TM
AU - Molyneaux,PL
AU - Noth,I
AU - Mutsaers,SE
AU - Prele,CM
AU - Peebles,RS
AU - Newcomb,DC
AU - Kaminski,N
AU - Blackwell,TS
AU - Van,Kaer L
AU - Drake,WP
DO - 10.1126/scitranslmed.aar8356
PY - 2018///
SN - 1946-6234
TI - PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production
T2 - Science Translational Medicine
UR - http://dx.doi.org/10.1126/scitranslmed.aar8356
UR - https://www.ncbi.nlm.nih.gov/pubmed/30257954
VL - 10
ER -