Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2011 Aug 1;187(3):1113-9. doi: 10.4049/jimmunol.1100056. Epub 2011 Jun 22.
The programmed death ligand 1 (PDL1)/programmed death 1 (PD1) costimulatory pathway plays an important role in the inhibition of alloimmune responses as well as in the induction and maintenance of peripheral tolerance. It has been demonstrated recently that PDL1 also can bind B7.1 to inhibit T cell responses in vitro. Using the bm12 into B6 heart transplant model, we investigated the functional significance of this interaction in alloimmune responses in vivo. PD1 blockade unlike PDL1 blockade failed to accelerate bm12 allograft rejection, suggesting a role for an additional binding partner for PDL1 other than PD1 in transplant rejection. PDL1 blockade was able to accelerate allograft rejection in B7.2-deficient recipients but not B7.1-deficient recipients, indicating that PDL1 interaction with B7.1 was important in inhibiting rejection. Administration of the novel 2H11 anti-PDL1 mAb, which only blocks the PDL1-B7.1 interaction, aggravated chronic injury of bm12 allografts in B6 recipients. Aggravated chronic injury was associated with an increased frequency of alloreactive IFN-γ-, IL-4-, and IL-6-producing splenocytes and a decreased percentage of regulatory T cells in the recipients. Using an in vitro cell culture assay, blockade of the interaction of PDL1 on dendritic cells with B7.1 on T cells increased IFN-γ production from alloreactive CD4(+) T cells, whereas blockade of dendritic cell B7.1 interaction with T cell PDL1 did not. These data indicate that PDL1 interaction with B7.1 plays an important role in the inhibition of alloimmune responses in vivo and suggests a dominant direction for PDL1 and B7.1 interaction.
程序性死亡配体 1（PDL1）/程序性死亡受体 1（PD1）共刺激途径在抑制同种免疫反应以及诱导和维持外周耐受方面起着重要作用。最近已经证明，PDL1 还可以结合 B7.1 来抑制体外 T 细胞反应。使用 bm12 到 B6 心脏移植模型，我们研究了这种相互作用在体内同种免疫反应中的功能意义。与 PDL1 阻断不同，PD1 阻断未能加速 bm12 同种异体移植物排斥，这表明在移植排斥中 PDL1 除了 PD1 之外还有其他结合伴侣。PDL1 阻断能够加速 B7.2 缺陷受体的同种异体移植物排斥，但不能加速 B7.1 缺陷受体的同种异体移植物排斥，表明 PDL1 与 B7.1 的相互作用在抑制排斥中很重要。施用新型 2H11 抗 PDL1 mAb，该 mAb 仅阻断 PDL1-B7.1 相互作用，加重了 B6 受体中 bm12 同种异体移植物的慢性损伤。加重的慢性损伤与同种反应性 IFN-γ-、IL-4-和 IL-6 产生的脾细胞频率增加以及受体中调节性 T 细胞的百分比降低有关。使用体外细胞培养测定，阻断树突状细胞上的 PDL1 与 T 细胞上的 B7.1 之间的相互作用增加了同种反应性 CD4(+)T 细胞的 IFN-γ 产生，而阻断树突状细胞 B7.1 与 T 细胞 PDL1 的相互作用则没有。这些数据表明，PDL1 与 B7.1 的相互作用在体内同种免疫反应的抑制中起着重要作用，并提示 PDL1 和 B7.1 相互作用的主导方向。
