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

Lindsay J Celada, Jonathan A Kropski, Jose D Herazo-Maya, Weifeng Luo, Amy Creecy, Andrew T Abad, Ozioma S Chioma, Grace Lee, Natalie E Hassell, Guzel I Shaginurova, Yufen Wang, Joyce E Johnson, Amy Kerrigan, Wendi R Mason, Robert P Baughman, Gregory D Ayers, Gordon R Bernard, Daniel A Culver, Courtney G Montgomery, Toby M Maher & 10 others Philip L Molyneaux, Imre Noth, Steven E Mutsaers, Cecilia M Prele, R Stokes Peebles, Dawn C Newcomb, Naftali Kaminski, Timothy S Blackwell, Luc Van Kaer, Wonder P Drake

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Article numbereaar8356
Number of pages15
JournalScience Translational Medicine
Volume10
Issue number460
DOIs
Publication statusPublished - 26 Sep 2018

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STAT3 Transcription Factor
Interleukin-17
Pulmonary Fibrosis
Transforming Growth Factors
Cell Death
Up-Regulation
T-Lymphocytes
Idiopathic Pulmonary Fibrosis
Collagen
Pulmonary Sarcoidosis
Bleomycin
Fibroblasts
Th17 Cells
Interstitial Lung Diseases
T-Lymphocyte Subsets
Coculture Techniques
Fibrosis
Transcription Factors
Immunohistochemistry
Lymphocytes

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Celada, L. J., Kropski, J. A., Herazo-Maya, J. D., Luo, W., Creecy, A., Abad, A. T., ... Drake, W. P. (2018). PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production. Science Translational Medicine, 10(460), [eaar8356]. https://doi.org/10.1126/scitranslmed.aar8356
Celada, Lindsay J ; Kropski, Jonathan A ; Herazo-Maya, Jose D ; Luo, Weifeng ; Creecy, Amy ; Abad, Andrew T ; Chioma, Ozioma S ; Lee, Grace ; Hassell, Natalie E ; Shaginurova, Guzel I ; Wang, Yufen ; Johnson, Joyce E ; Kerrigan, Amy ; Mason, Wendi R ; Baughman, Robert P ; Ayers, Gregory D ; Bernard, Gordon R ; Culver, Daniel A ; Montgomery, Courtney G ; Maher, Toby M ; Molyneaux, Philip L ; Noth, Imre ; Mutsaers, Steven E ; Prele, Cecilia M ; Stokes Peebles, R ; Newcomb, Dawn C ; Kaminski, Naftali ; Blackwell, Timothy S ; Van Kaer, Luc ; Drake, Wonder P. / PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production. In: Science Translational Medicine. 2018 ; Vol. 10, No. 460.
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title = "PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production",
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.",
author = "Celada, {Lindsay J} and Kropski, {Jonathan A} and Herazo-Maya, {Jose D} and Weifeng Luo and Amy Creecy and Abad, {Andrew T} and Chioma, {Ozioma S} and Grace Lee and Hassell, {Natalie E} and Shaginurova, {Guzel I} and Yufen Wang and Johnson, {Joyce E} and Amy Kerrigan and Mason, {Wendi R} and Baughman, {Robert P} and Ayers, {Gregory D} and Bernard, {Gordon R} and Culver, {Daniel A} and Montgomery, {Courtney G} and Maher, {Toby M} and Molyneaux, {Philip L} and Imre Noth and Mutsaers, {Steven E} and Prele, {Cecilia M} and {Stokes Peebles}, R and Newcomb, {Dawn C} and Naftali Kaminski and Blackwell, {Timothy S} and {Van Kaer}, Luc and Drake, {Wonder P}",
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Celada, LJ, Kropski, JA, Herazo-Maya, JD, Luo, W, Creecy, A, Abad, AT, Chioma, OS, Lee, G, Hassell, NE, Shaginurova, GI, Wang, Y, Johnson, JE, Kerrigan, A, Mason, WR, Baughman, RP, Ayers, GD, Bernard, GR, Culver, DA, Montgomery, CG, Maher, TM, Molyneaux, PL, Noth, I, Mutsaers, SE, Prele, CM, Stokes Peebles, R, Newcomb, DC, Kaminski, N, Blackwell, TS, Van Kaer, L & Drake, WP 2018, 'PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production' Science Translational Medicine, vol. 10, no. 460, eaar8356. https://doi.org/10.1126/scitranslmed.aar8356

PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production. / Celada, Lindsay J; Kropski, Jonathan A; Herazo-Maya, Jose D; Luo, Weifeng; Creecy, Amy; Abad, Andrew T; Chioma, Ozioma S; Lee, Grace; Hassell, Natalie E; Shaginurova, Guzel I; Wang, Yufen; Johnson, Joyce E; Kerrigan, Amy; Mason, Wendi R; Baughman, Robert P; Ayers, Gregory D; Bernard, Gordon R; Culver, Daniel A; Montgomery, Courtney G; Maher, Toby M; Molyneaux, Philip L; Noth, Imre; Mutsaers, Steven E; Prele, Cecilia M; Stokes Peebles, R; Newcomb, Dawn C; Kaminski, Naftali; Blackwell, Timothy S; Van Kaer, Luc; Drake, Wonder P.

In: Science Translational Medicine, Vol. 10, No. 460, eaar8356, 26.09.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

AU - Celada, Lindsay J

AU - Kropski, Jonathan A

AU - Herazo-Maya, Jose D

AU - Luo, Weifeng

AU - Creecy, Amy

AU - Abad, Andrew T

AU - Chioma, Ozioma S

AU - Lee, Grace

AU - Hassell, Natalie E

AU - Shaginurova, Guzel I

AU - Wang, Yufen

AU - Johnson, Joyce E

AU - Kerrigan, Amy

AU - Mason, Wendi R

AU - Baughman, Robert P

AU - Ayers, Gregory D

AU - Bernard, Gordon R

AU - Culver, Daniel A

AU - Montgomery, Courtney G

AU - Maher, Toby M

AU - Molyneaux, Philip L

AU - Noth, Imre

AU - Mutsaers, Steven E

AU - Prele, Cecilia M

AU - Stokes Peebles, R

AU - Newcomb, Dawn C

AU - Kaminski, Naftali

AU - Blackwell, Timothy S

AU - Van Kaer, Luc

AU - Drake, Wonder P

N1 - Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PY - 2018/9/26

Y1 - 2018/9/26

N2 - 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.

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.

U2 - 10.1126/scitranslmed.aar8356

DO - 10.1126/scitranslmed.aar8356

M3 - Article

VL - 10

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 460

M1 - eaar8356

ER -