4-1BBL/4-1BB信号介导肠上皮γδT细胞诱导、扩增Treg抑制肾移植慢性排斥及机制研究

It is showed in research that the production of endogenous antigen-specific regulatory T cells (Treg) can be induced via oral administration of donor antigen. But the mechanism remains unknown. Our prior work shows that intraepithelial γδT cells can not only directly induce the production of Tregs in vitro but also can stimulate the proliferation. It is reported in the literature that the proliferation of Tregs can be stimulated in vitro by the co-work of the costimulatory signal of 4-1 BBL / 4-1 BB and IL2 which can be expressed and secreted after the activation of intraepithelial γδT cells. It is a clue that 4-1 BBL / 4-1 BB may play a key role in the process of stimulating the proliferation of Tregs by intraepithelial γδT cells. Our research firstly focuses on the exploration of the role of 4-1BB/4-1BBL costimulatory signal in preventing the chronic rejection episode of renal allografts by intraepithelial γδ T cells via oral administration of donor antigen in the kidney transplantation model in mice.Then it will be discussed that whether Tregs can be expanded by the stimulation of the signal.Finally, to explore the molecular mechanism of 4-1BB/4-1BBL costimulatory signal in expansion of Tregs by intraepithelial γδ T cells to improve the efficiency of induction of Tregs via oral administration of donor antigen and lay the foundation for the treatment of chronic rejection.

研究显示口服移植物抗原可内源性诱导抗原特异性调节性T细胞(Treg)产生，抑制排斥反应。但口服抗原体内诱导和扩增Treg的机制不明。我们前期工作表明，肠上皮γδT细胞不但能在体外直接诱导Treg产生，还能够 刺激Treg增殖。文献报道4-1BBL/4-1BB共刺激信号和IL2共同作用能够在体内外刺激Treg扩增，而肠上皮γδ T细胞高激活后表达4-1BBL分子和分泌IL2。提示4-1BBL/4-1BB共刺激信号在肠上皮γδT细胞刺激Treg增殖过 程中可能起关键作用。本研究拟通过体外模型探讨4-1BBL/4-1BB刺激信号在肠上皮γδT细胞体内扩增Treg中的作用机制，为提高口服抗原诱导Treg的效率，治疗慢性排斥反应奠定基础。

研究显示口服移植物抗原可内源性诱导抗原特异性调节性T细胞(Treg)产生，抑制排斥反应。但口服抗原体内诱导和扩增Treg的机制不明。我们前期工作表明，肠上皮γδT细胞不但能在体外直接诱导Treg产生，还能够 刺激Treg增殖。文献报道4-1BBL/4-1BB共刺激信号和IL2共同作用能够在体内外刺激Treg扩增，而肠上皮γδ T细胞高激活后表达4-1BBL分子和分泌IL2。提示4-1BBL/4-1BB共刺激信号在肠上皮γδT细胞刺激Treg增殖过 程中可能起关键作用。本研究通过建立小鼠胰岛移植模型，明确了肠上皮γδT细胞膜分子4-1BBL在口服抗原减轻移植物排斥反应中的作用；证实了4-1BBL/4-1BB刺激信号在肠上皮γδT细胞体内扩增Treg中的关键作用。