CD70 Activation Decreases Pulmonary Fibroblast Production of Extracellular Matrix Proteins.

Academic Article

Abstract

  • Idiopathic pulmonary fibrosis (IPF) is a lethal, medically refractory syndrome characterized by intrapulmonary accumulations of extracellular matrix (ECM) proteins produced by fibroblasts. Activation, clonal expansions, and differentiation of lymphocytes are also frequently present in IPF. Activated T-cells are known to exert several effects that promote ECM production, but opposing homeostatic actions, wherein T-cells can inhibit fibrosis, are less well understood. We found CD27, a TNF receptor ubiquitously expressed on naïve T-cells, is downregulated on CD4 T-cells of IPF patients and CD70, the sole ligand for CD27, is present on human pulmonary fibroblasts. We hypothesized cognate engagements between lymphocyte CD27 and fibroblast CD70 could have functional consequences. Accordingly, a series of subsequent studies were conducted to examine the possible role of CD27-CD70 interactions in the regulation of fibrogenesis. Using immunoblotting, flow cytometry, RT-PCR, and kinomic assays, we found fibroblast CD70 expression was inversely correlated with cell density, and upregulated by TGF-β1. CD70 agonists, including T-cell-derived soluble CD27, markedly diminished fibroblast collagen and fibronectin synthesis, and these effects were potent enough to also inhibit pro-fibrotic actions of TGF-β1 on ECM production in vitro and in two distinct ex vivo human skin models. CD70 activation was mediated by AKT and complex interconnected signaling pathways, and was abated by prior CD70 knockdown. These results show the CD70/CD27 axis modulates T cell-fibroblast interactions, and may be an important regulator of fibrosis and wound healing. Fibroblast CD70 could also be a novel target for specific, mechanistically-based anti-fibrosis treatments.
  • Authors

    Keywords

  • Fibroblasts, Pulmonary Fibrosis, T-cells
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    Author List

  • Tran-Nguyen TK; Xue J; Feghali-Bostwick C; Sciurba FC; Kass DJ; Duncan SR