NKT细胞是特殊的T细胞亚群，有抑制性免疫调节作用,供者和宿主NKT细胞均能预防移植物抗宿主病（GVHD），但确切机制未明。新发现的髓系来源抑制性细胞（MDSCs）是一类髓系起源的异质群体，有免疫抑制功能，供者MDSCs能够减轻骨髓移植后的GVHD。前期研究发现在CD3单抗预处理方案预防GVHD的模型中，受者组织中有高比例的宿主NKT细胞和MDSCs。预实验发现NKT细胞可抑制供者CD8T细胞增殖和迁移。我们推测宿主NKT细胞与宿主MDSCs的相互作用进而影响供者T细胞的增殖和迁移，以达到预防GVHD目的。有基于此，本研究利用CD3单抗预处理预防GVHD的模型，研究宿主NKT细胞是否与宿主MDSCs相互作用，引起T细胞增殖下降并下调表达趋化因子受体/归巢受体，导致供者T细胞迁移到靶器官受阻,达到揭示预防GVHD机制，并利用转化医学的手段，为NKT细胞应用于临床输注预防GVHD提供实验依据。

Natural killer T (NKT) cells are special T cells which play roles in suppressive immunoregulation. Both host and donor NKT cells have been reported to prevent graft-versus-host disease (GVHD). However, the exact mechanism of the prevention is still unclear. The newly discovered myeloid-derived suppressor cells (MDSCs) is a population of CD11b+Gr-1+ myeloid cells which also play roles in suppressive immunoregulation. It is reported that donor MDSCs can ameliorate GVHD after allo-HSCT. Our previous study found that host type of NKT and MDSCs maintained a high proportion after HSCT in an anti-CD3 mAb conditioning regimen mouse model for prevention of GVHD. Our pilot study found that NKT cells inhibited donor CD8T cell proliferation and migration into GVHD target tissue. We hypothesis that the interaction of host NKT cells and host MDSCs can influence the proliferation and migration of donor T cells, which prevent GVHD. Therefore, in this study, we will study the interaction of host NKT cells and host MDSCs in our anti-CD3 mAb conditioning regimen mouse model for prevention of GVHD. We will test whether the interaction of host NKT cells and host MDSCs inhibits donor T cell proliferation and downregulation of expression of chemokine receptor/homing receptor, which lead to less migration of donor T cells into GVHD target tissue. We will try to find out the role of NKT cells in suppressive immunoregulation of graft-versus-host disease and use the translational medicine methods for the infusion of NKT cells to prevent/ameliorate GVHD.

NKT细胞是特殊的T细胞亚群，有抑制性免疫调节作用,供者和宿主NKT细胞均能预防移植物抗宿主病（GVHD），但确切机制未明。本研究利用CD3单抗预处理预防GVHD的模型，研究宿主NKT细胞下调T细胞表达趋化因子受体/归巢受体，导致供者T细胞迁移到靶器官受阻,达到揭示预防GVHD机制，探讨宿主NKT 细胞减弱/预防GVHD 的作用是否经由IL-4 介导。通过NKT缺陷小鼠（CD1d-），加回NKT细胞，IL4缺陷小鼠作为工具，以体内体外实验作为手段，我们发现，(1)宿主NKT细胞在调节供体CD8+T细胞组织迁移起关键作用；(2)宿主NKT调节趋化因子及其受体的表达和供体T细胞迁移的是IL-4部分依赖的；(3)NKT调节供者 T淋巴细胞表达趋化因子受体是自身分泌的IL-4依赖的。本项目经过一年研究，基本完成了项目计划的研究内容。发表1篇论著，1篇综述待刊。