Pseudoreceptor BAMBI As A New Strategy For Abnormal Differentiation Of Regulatory T Cells In COPD

Part ? TGF-?/BAMBI pathway dysfunction contributes to peripheral Th17/Treg imbalance in chronic obstructive pulmonary diseaseBMP and activin membrane-bound inhibitor(BAMBI)is postulated to inhibit or modulate transforming growth factor ?(TGF-?)signaling.Furthermore,strong upregulation of BAMBI expression following in vitro infection of chronic obstructive pulmonary disease(COPD)lung tissue has been demonstrated.In this study,we investigated whether TGF-?/BAMBI pathway is associated with COPD.Blood samples were obtained from 27 healthy controls(HC),24 healthy smokers(HS)and 29 COPD patients.Elevated Thl7/Treg ratios,and increased levels of BAMBI protein and mRNA(in plasma and CD4+T cells respectively),were observed in COPD compared with HC and HS.BAMBI expression was first observed on human CD4+ T cells,with a typical membrane-bound pattern.The enhanced plasma BAMBI levels in COPD positively correlated with the increased plasma TGF-?1 levels and Th17/Treg ratio.Together.an impaired TGF-?/BAMBI pathway may promote the inflammation leading to Th17/Treg imbalance.which is a new mechanism in smokers who develop COPD.Part II Reciprocal regulation of Thl7/Treg cells by cigarette smoke extract through the pseudoreceptor BAMBIIn CD4+ T helper(Th)cells,transforming growth factor ?1(TGF-?1)is indispensable for induction of both regulatory T(Treg)and Thl7 cells.Although BAMBI(BMP and activin membrane-bound inhibitor)has been identified as part of a rheostat-like mechanism for regulation of TGF-? signaling and autoimmune arthritis in mice model,the underlying activity of BAMBI in human Th17/Treg axis,especially during exposure to cigarette smoke,remains to be well elucidated.In this study,the characterization of Tregs and Th17 differentiation upon cigarette smoke extract(CSE)exposure were determined by flow cytometry.Furthermore,the effects of CSE on Smad2/3 phosphorylation and BAMBI expression in TCR-stimulated naive cells were also evaluated.Our study demonstrated that CSE exposure caused the partial suppression of Treg differentiation and the promotion of Th17 generation under stimulation by anti-CD3/28 antibodies plus TGF-?1.Meanwhile,cigarette smoke brought a dose-dependent inhibition of p-Smad2/3 which could arise from a concomitant enhancement of BAMBI expression.In conclusion,human BAMBI functions as a molecular switch to control TGF-(3 signaling strength and Thl7/Treg balance,which could be not only used as a biomarker,but also as a target of new treatment strategies for maintaining immune tolerance and for treatment of smoking-induced immune disorders.