AUTHOR=Peng Xueyan , Moore Meagan W. , Peng Hong , Sun Huanxing , Gan Ye , Homer Robert J. , Herzog Erica L. 

TITLE=CD4+CD25+FoxP3+ Regulatory Tregs inhibit fibrocyte recruitment and fibrosis via suppression of FGF-9 production in the TGF-β1 exposed murine lung

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 5 - 2014

YEAR=2014

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2014.00080

DOI=10.3389/fphar.2014.00080

ISSN=1663-9812

ABSTRACT=Pulmonary fibrosis is a difficult to treat, often fatal disease whose pathogenesis involves  dysregulated TGF-b1 signaling. CD4+CD25+FoxP3+ Regulatory T cells (“Tregs”) exert important effects on host tolerance and arise from naïve CD4+ lymphocytes in response to TGF-b1.  However the precise contribution of Tregs to experimentally induced murine lung fibrosis remains unclear.  We sought to better understand the role of Tregs in this context.  Using a model of fibrosis caused by lung specific inducible overexpression of the bioactive form of the human TGF-b1 gene we find that Tregs accumulate in the lung parenchyma within five days of transgene activation and that this enhancement persists to at least fourteen days. Anti-CD25 Antibody mediated depletion of Tregs causes increased detection of soluble collagen and of intrapulmonary CD45+CD34+Col Ia1 fibrocytes.  These findings are accompanied by enhanced local concentrations of the classical inflammatory mediators CD40L, TNF-a, and IL-1a, along with the neuroimmune molecule fibroblast growth factor 9 (FGF-9, also known as “glial activating factor”). FGF-9 expression localizes to structural cells and alveolar macrophages in this model and antibody mediated neutralization of FGF-9 results in attenuated detection of intrapulmonary collagen and fibrocytes without affecting Treg quantities. These data indicate that CD4+CD25+FoxP3+ Tregs attenuate TGF-b1 induced lung fibrosis and fibrocyte accumulation in part via suppression of FGF-9.