CD226分子调控Treg细胞分化增殖参与同种异体移植物耐受机制的研究

Transplantation is the treatment of choice for most patients with end-stage solid organ diseases, resulting in dramatic improvement in morbidity and mortality. Clinical tolerance induction to permit minimization or cessation of immunosuppressive drugs is one of the key research goals in solid organ transportation. It has been reported that CD226 control the induction of GVHD after BMT and that although CD226-dependent costimulatory effects on CD8 T cells are redundant. How the CD226 control the expansion and functions of Foxp3+ Treg cell in solid organ transplantation are still unknown. CD226 molecule is an adhesion/costimulatory molecule belonging to the immunoglobulin super-family, expressed in a variety subsets of immune cells. CD226 involved in the development, differentiation, proliferation and function of lymphocytes. In our previous study, we found that the CD226 knockout mice showed resistance to a variety of inflammatory disease; CD226 antibody could suppress autoimmune disease progression, and could suppress allograft rejection, prolonging graft survival. The suppress function of CD226 antibody maybe associate with the production of inhibitory cytokines such as IL-10, and Treg cells proliferation, which hinted that CD226 has potential application value in controlling graft rejection. In this study, we plan to investigate the mechanism of CD226 involved in the transplant immune rejection, clarifying the mechanisms of how CD226 regulating the Tregs functions; and provide new possibility of intervention CD226 signal to induce transplantation tolerance.

探索移植免疫调控机制、开发新的免疫干预策略，是器官移植领域研究重点；共刺激分子和调节性T细胞（Treg）作用机制研究具有良好的临床应用前景。CD226分子表达于多种免疫细胞，参与其发育分化、增殖杀伤等功能调控，在肿瘤、自身免疫病、移植排斥等领域获得越来越多的重视。本课题组长期从事CD226结构与功能研究。我们发现，CD226敲除小鼠表现出对多种炎症性疾病的抵抗；CD226抗体可抑制自身免疫性疾病进展，可抑制同种异体移植排斥，延长移植物生存期，其机制与上调IL-10等抑制性细胞因子、促进Treg细胞扩增有关，提示CD226在控制移植物排斥方面具有潜在应用价值。本课题拟深入探讨同种异体移植排斥反应中CD226与移植物耐受的关系，阐明CD226调控Treg细胞分化增殖的分子通路，以及诱导Treg细胞促进免疫耐受的可能机制，为移植排斥反应的基础研究和免疫治疗提供新思路和新靶点。

本课题进展基本按照预定方案执行，研究了CD226分子调控调节性T细胞的分子机制，及其在同种异体移植等炎症性疾病中的作用。本课题实施基本完成了原定研究目标的全部内容。实验发现，CD226信号对于nTreg细胞在胸腺的发育和外周naïve T细胞向iTreg的分化的均具有重要的调节作用，CD226、TIGIT分子活化和抑制信号的平衡可能是CD226参与Treg细胞分化和抑制效应调控的重要因素。阐明了CD226分子信号途径促进移植排斥反应中Treg细胞优先分化增殖的作用，确定干预CD226分子信号途径、促进Treg细胞功能活性的技术方案，为基于Treg细胞诱导异基因移植物耐受的应用基础研究提供实验证据和理论依据。并基于CD226条件性敲除小鼠的炎症性疾病模型，探讨了CD226分子对于Treg和其他免疫细胞功能调控的分子机制。. 主要研究内容包括：阐明同种异体移植排斥过程中外周Treg细胞比例增加与CD226分子表达水平的关系，明确CD226/TIGIT-CD155分子间相互作用对于Treg细胞的发育和分化的重要调控效应；探讨了CD226分子信号途径促进移植排斥反应中Treg细胞优先分化增殖的作用，深入研究CD226、TIGIT竞争结合CD155、调控Treg细胞分化增殖的分子机制；明确了CD226分子促进移植物抗原特异性Treg细胞优先分化增殖的分子机制；确定了采用CD226-Fc重组蛋白干预CD226分子信号途径、促进Treg细胞功能活性的技术方案，为基于Treg细胞诱导异基因移植物耐受的应用基础研究提供实验证据和理论依据。