假受体BAMBI：COPD 调节性T细胞分化异常的新机制

The fact that our patients with COPD have nonnormal differentiation of T cells was founded in our previous works. Although TGF-β increased significantly in patients with COPD, However, The anti-inflammatory differentiation of CD25+FoxP3+ T cells （Treg） decreased simultaneously. The mechanism of the results was unclear. This program will be based on our previous works to further investigate the new function of pseudoreceptor of TGF-β BAMBI on nonnormal differentiation of Treg in patients with COPD. (1) Ascertain the profiles of BAMBI in different T cell subsets ,especially in Treg of various population; and relationship between BAMBI and other cytokines and T cell subsets;(2)Define the effects of smoking on expression of BAMBI in Treg; (3)Investigate the impact of high or low expression of BAMBI on proliferation,differentiation,apoptosis of Treg and function of Treg; （4）Clarify the mechanism of aciton of BAMBI in Treg, reveal its molecular mechanism of negative feedback regulation and signaling pathway; (5) Identify the clinical significance of BAMBI in diagnosis, evaluation of therapeutic efficacy and prognosis of patients with COPD. The accomplishment of this program will elucidate the new mechanism of nonnormal inflammatory reaction in patients with COPD for the first time, provide new strategy for prevention and management of COPD, offer new target for therapy.

我们前期工作发现，COPD的T细胞分化异常，TGF-β显著增多，但表达FoxP3+调节性T细胞（Treg）分化减少，机制不明。本项目将在此基础上，研究TGF-β的假受体BAMBI在Treg分化异常中的作用新机制:(1)查明BAMBI在正常人、吸烟和COPD组Treg中的表达状态 ,与T细胞亚群和细胞因子的关系；(2) 研究吸烟对Treg的BAMBI表达的影响；(3) 探讨BAMBI高低表达对Treg诱导分化、增殖、凋亡和功能的影响；(4) 阐明BAMBI细胞内作用机制，明确BAMBI影响Treg诱导分化、增殖、凋亡和功能所利用的信号转导途径，揭示其负反馈调节作用的分子机制；(5) 明确BAMBI在诊断和预后评估中的临床价值。本项目的完成将首次阐明COPD异常炎症反应的部分新机制，为防治COPD提出新的策略，新的治疗靶点。

慢阻肺患者的T细胞分化异常，TGF-β显著增多，但FoxP3+调节性T细胞（Treg）分化减少，机制不明。本项目研究了TGF-β的假受体BAMBI在Treg分化异常中的作用新机制。结果显示，与健康对照组和吸烟肺功能正常组相比，COPD患者外周血的Th17/Treg比例升高，且BAMBI蛋白（在血浆中）和mRNA（在CD4+T细胞中）水平亦显著升高。我们首次发现BAMBI在人CD4+T细胞中表达，且呈现典型的膜结合型。COPD患者上调的血浆BAMBI水平不但与增加的血浆TGF-β1呈正相关，还与增加的Th17/Treg比例呈正相关。总之，TGF-β/BAMBI通路障碍可能导致炎症反应以及Th17/Treg失衡，这可能是吸烟者发展为COPD的新机制。另外，本研究发现，在抗CD3/28抗体和TGF-β1的共同作用下，香烟提取物（CSE）暴露能够部分抑制Treg分化并促进Th17分化。同时，CSE能以剂量依赖性的方式抑制p-Smad2/3，这可能是由于伴随的BAMBI表达上调所致。总之，BAMBI能够作为分子开关来控制TGF-β信号强度和Th17/Treg平衡，因而BAMBI不仅可以作为一种生物标志，而且还能作为维持免疫耐受和吸烟诱导的免疫疾病的全新治疗靶点。