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.

Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity

“…S3b ). The most dramatic findings in fibrotic lung samples were the increased percentages of regulatory T cells (Treg) and PD-1+CD4+ T cells 40 ( Fig. 3c, d and Supplementary Fig.…”

“…Clinically, CD47 and PD-L1 are of interest because excellent reagents have already been developed by multiple pharmaceutical companies to target both immune checkpoint molecules. Antibody therapies against both are currently being tested in clinical trials for cancer 31,32,39,40 , and a blocking antibody against IL-6 is FDA approved to treat rheumatoid arthritis and acute cytokine release syndrome, a side effect of CAR-T cell therapy 33 . Therefore, extensive safety information will become available from these cancer studies.…”

Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD‐L1 into extracellular vesicles

“…Programed death-ligand 1 is highly expressed in various human cancers and promotes T cell tolerance or escape from host immunity. 60 While PD-L1 is known to be expressed in fibroblasts, [61][62][63][64] to the best of our understanding, there is no evidence which connects PD-L1 expression with TGFβ and fibrogenesis. TGFβ is considered as one of the most profibrotic cytokines and it is well established that TGFβ is a crucial modulator of ECM production in fibrogenic processes.…”

Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance inKRAS/p53mutant lung cancers

“…S3A and S3B). Th17 cells are a subset of pro-inflammatory CD4 + T cells that express RORγt and secrete the tumorpromoting cytokines IL-17 and IL-22 12,17,18,19,20,21,22,23,24,25 . Nanostring analysis of 344SQ tumors that were responsive and resistant to combinatorial treatment confirmed our qPCR array, showing a significant upregulation of IL-17F in resistant 344SQ tumors ( Supplementary Fig.…”