MIC-1诱导外周血naive CD4+T细胞向 iTreg分化的机制研究

T regulatory cell (Treg) is a constitutively immunosuppressive T cell type contributing to the maintenance of immunological self-tolerance and immune homeostasis. Treg cells have the ability to promote tumor progress and accelerate immune escape. It was reported that multiple molecular derived from tumor involved in Tregs differentiation and function, but the key molecular is still unclear. We screened human colon tumor T7 phage cDNA library for proteins derived from colonic cancer cells that potentially interacted with na?ve CD4+T cells. Our results revealed that, 1. MIC-1 showed high affinity with na?ve CD4+T cells. 2. MIC-1 expression level was closely correlated with the TNM stages of colon cancer patients. 3. MIC-1 could induce na?ve CD4+T cells differentiate to iTregs. The results above demonstrated that MIC-1 may play an important role in Tregs induction and immune escape process of colon cancer. Through what means did MIC-1 induced iTreg differentiation and what is the exact molecular mechanism? Answering above questions will find the new mechanism for Treg differentiation and the new immunotherapy target for colon cancer.

调节性T细胞（Treg）是一类具有免疫抑制功能的T淋巴细胞亚群，它在维持免疫系统自稳、调节机体免疫应答中发挥着重要的功能。研究显示其能促进肿瘤的进展及免疫逃逸，并且多种肿瘤相关因子与Treg细胞的分化及功能相关，然而关键作用分子及其机制仍未阐明。我们课题组在前期实验中应用噬菌体展示文库技术从结肠癌筛选了一系列可与na?ve CD4+T细胞结合的候选分子并对其进行了功能确认。结果显示：1、巨噬细胞抑制性细胞因子1（MIC-1）与na?ve CD4+T呈现了高亲和性；2、MIC-1表达水平与结肠癌患者TNM分期呈正相关；3、MIC-1能诱导na?ve CD4+T细胞向iTreg转化。上述结果提示MIC-1在Treg分化及结肠癌的免疫逃逸中可能发挥重要作用，那么其如何发挥诱导分化功能，具体分子机制又是什么？对上述问题的回答将为Treg分化提供新的机制，为结肠癌的肿瘤免疫治疗提供新的靶点。

调节性T细胞（Treg）是一类具有免疫抑制功能的T淋巴细胞亚群，它在维持免疫系统自稳、调节机体免疫应答中发挥着重要的功能。研究显示其能促进肿瘤的进展及免疫逃逸，并且多种肿瘤相关因子与Treg细胞的分化及功能相关，然而关键作用分子及其机制仍未阐明。我们课题组在前期实验中应用噬菌体展示文库技术从结肠癌筛选了一系列可与naive CD4+T细胞结合的候选分子并对其进行了功能确认。我们研究发现巨噬细胞抑制性细胞因子1（MIC-1，又称为GDF-15）与naive CD4+T呈现了高亲和性，MIC-1表达水平与结肠癌患者TNM分期呈正相关，MIC-1能诱导naive CD4+T细胞向iTreg转化,诱导分化后的iTreg具有Treg的表型和功能。并进一步通过Co-IP结合质谱分析，初步获得MIC-1受体的候选分子。分子机制研究发现， MIC-1通过活化Smad并抑制ERK信号通路，引起转录因子E2A表达增高并结合Foxp3启动子，从而上调Foxp3表达，促进iTregs分化。上述结果首次揭示MIC-1能够通过与naïve CD4+T细胞相互作用，诱导其向iTreg的分化，为MIC-1在肿瘤发生发展中的复杂的生物学作用提供新的线索，也为肿瘤的免疫逃逸提供新的机制，为肿瘤的免疫治疗提供新的靶点。