Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 296 Campus Drive, Stanford, CA 94305, USA.
Blood. 2012 Feb 9;119(6):1581-9. doi: 10.1182/blood-2011-08-371948. Epub 2011 Dec 15.
We used a model of combined bone marrow and heart transplantation, in which tolerance and stable chimerism is induced after conditioning with fractionated irradiation of the lymphoid tissues and anti-T-cell antibodies. Graft acceptance and chimerism required host CD4(+)CD25(+) Treg production of IL-10 that was in-turn enhanced by host invariant natural killer (NK) T-cell production of IL-4. Up-regulation of PD-1 on host Tregs, CD4(+)CD25(-) conventional T (Tcon) cells, and CD8(+) T cells was also enhanced by NKT cell production of IL-4. Up-regulated PD-1 expression on Tregs was linked to IL-10 secretion, on CD8(+) T cells was linked to Tim-3 expression, and on CD4(+) Tcon cells was associated with reduced IFNγ secretion. Changes in the expression of PD-1 were induced by the conditioning regimen, and declined after bone marrow transplantation. In conclusion, NKT cells in this model promoted changes in expression of negative costimulatory receptors and anti-inflammatory cytokines by Tregs and other T-cell subsets in an IL-4-dependent manner that resulted in tolerance to the bone marrow and organ grafts.
我们使用了一种骨髓和心脏联合移植的模型，在该模型中，通过对淋巴组织进行分次照射和抗 T 细胞抗体进行预处理，可以诱导耐受和稳定的嵌合体。移植物接受和嵌合体需要宿主 CD4+CD25+Treg 产生 IL-10，而宿主不变自然杀伤 (NK) T 细胞产生的 IL-4 反过来又增强了这一作用。宿主 Treg、CD4+CD25-常规 T（Tcon）细胞和 CD8+T 细胞上 PD-1 的上调也被 NK T 细胞产生的 IL-4 增强。Treg 上上调的 PD-1 表达与 IL-10 分泌相关，CD8+T 细胞上上调的 PD-1 表达与 Tim-3 表达相关，CD4+Tcon 细胞上上调的 PD-1 表达与 IFNγ 分泌减少相关。PD-1 的表达变化是由预处理方案诱导的，并在骨髓移植后下降。总之，在该模型中，NKT 细胞以 IL-4 依赖的方式促进了 Treg 和其他 T 细胞亚群上负共刺激受体和抗炎细胞因子表达的变化，从而导致对骨髓和器官移植物的耐受。
