Title: Activated human T lymphocytes inhibit TGFβ-induced fibroblast to myofibroblast differentiation via prostaglandins D2 and E2.

Authors: Lacy, Shannon H; Epa, Amali P; Pollock, Stephen J; Woeller, Collynn F; Thatcher, Thomas H; Phipps, Richard P; Sime, Patricia J

Published In Am J Physiol Lung Cell Mol Physiol, (2018 04 01)

Abstract: In pulmonary fibrosis (PF), fibroblasts and myofibroblasts proliferate and deposit excessive extracellular matrix in the interstitium, impairing normal lung function. Because most forms of PF have a poor prognosis and limited treatment options, PF represents an urgent unmet need for novel, effective therapeutics. Although the role of immune cells in lung fibrosis is unclear, recent studies suggest that T lymphocyte (T cell) activation may be impaired in PF patients. Furthermore, we have previously shown that activated T cells can produce prostaglandins with anti-scarring potential. Here, we test the hypothesis that activated T cells directly inhibit myofibroblast differentiation using a coculture system. Coculture with activated primary blood-derived T cells, from both healthy human donors and PF patients, inhibited transforming growth factor β-induced myofibroblast differentiation in primary human lung fibroblasts isolated from either normal or PF lung tissue. Coculture supernatants contained anti-fibrotic prostaglandins D2 and E2, and the inhibitory effect of coculture on myofibroblast differentiation was largely reversed when prostaglandin production was abrogated either by resting the T cells before coculture or via specific pharmacological inhibitors. Moreover, coculture conditions induced COX-2 in HLFs but not in T cells, suggesting that T cells deliver an activating signal to HLFs, which in turn produce anti-fibrotic prostaglandins. We show for the first time that coculture with activated primary human T lymphocytes strongly inhibits myofibroblast differentiation, revealing a novel cell-to-cell communication network with therapeutic implications for fibrotic lung diseases.

PubMed ID: 29351444

MeSH Terms: Cell Differentiation/drug effects*; Cells, Cultured; Coculture Techniques; Dinoprostone/metabolism*; Fibroblasts/drug effects; Fibroblasts/metabolism; Fibroblasts/pathology*; Humans; Myofibroblasts/drug effects; Myofibroblasts/metabolism; Myofibroblasts/pathology*; Prostaglandin D2/metabolism*; Pulmonary Fibrosis/metabolism; Pulmonary Fibrosis/pathology; T-Lymphocytes/immunology*; T-Lymphocytes/metabolism; T-Lymphocytes/pathology; Transforming Growth Factor beta/pharmacology*