McGee Halvor S, Yagita Hideo, Shao Zhifei, Agrawal Devendra K
Department of Biomedical Sciences, Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA.
Am J Respir Cell Mol Biol. 2010 Oct;43(4):432-42. doi: 10.1165/rcmb.2009-0258OC. Epub 2009 Nov 9.
We recently reported that the adoptive transfer of T-regulatory cells (Tregs) isolated from lung and spleen tissue of green fluorescent protein-transgenic mice reversed airway hyperresponsiveness and airway inflammation. Because Programmed Death-1 (PD-1) is a pivotal receptor regulating effector T-cell activation by Tregs, we evaluated whether PD-1 is involved in the therapeutic effect of naturally occurring Tregs (NTregs) and inducible Tregs (iTregs) in cockroach (CRA)-sensitized and challenged mice. The CD4(+)CD25(+) NTregs and CD4(+)CD25(-) iTregs isolated from the lungs and spleens of BALB/c mice were adoptively transferred into CRA-sensitized and CRA-challenged mice with and without anti-PD-1 antibody (100 μg/mice). The CD4(+)CD25(+) T cells in the lung were phenotyped after adoptive transfer. Concentrations of IL-4, IL-5, IL-10, IFN-γ, and IL-13 in bronchoalveolar lavage fluid (BALF) were measured using ELISA. The NTregs and iTregs from either lung or spleen tissue reversed airway hyperresponsiveness for at least 4 wk. However, the therapeutic effect was blocked by administering the anti-PD-1 antibody. The administration of Tregs-recipient mice with anti-PD-1 antibody significantly decreased cytotoxic T-lymphocyte antigen-4 expression, with low concentrations of Forkhead-winged transcriptional factor box 3 (Foxp3) mRNA transcripts in lung CD4(+)CD25(+) T cells. These mice had substantially higher concentrations of BALF IL-4, IL-5, and IL-13, but significantly decreased levels of BALF IL-10. Adoptive therapy recipients without the anti-PD-1 antibody exhibited high levels of CTLA-4 expression and Foxp3 transcripts in lung CD4(+)CD25(+) T cells, with a significant decrease in BALF IL-4, IL-5, and IL-13 concentrations and a substantial increase in BALF IL-10 concentrations. These data suggest that the reversal of airway hyperresponsiveness and airway inflammation by Tregs is mediated in part by PD-1, because other costimulatory molecules (e.g., inducible costimulatory molecule [ICOS] or CTLA-4) have been shown to play a role in Treg-mediated suppression.
我们最近报道，从绿色荧光蛋白转基因小鼠的肺和脾组织中分离出的调节性T细胞（Tregs）进行过继转移，可逆转气道高反应性和气道炎症。由于程序性死亡1（PD-1）是一种调节Tregs对效应T细胞激活的关键受体，我们评估了PD-1是否参与天然调节性T细胞（NTregs）和诱导性调节性T细胞（iTregs）对蟑螂（CRA）致敏并激发的小鼠的治疗作用。将从BALB/c小鼠的肺和脾中分离出的CD4(+)CD25(+) NTregs和CD4(+)CD25(-) iTregs过继转移到有或没有抗PD-1抗体（100μg/小鼠）的CRA致敏并CRA激发的小鼠体内。过继转移后对肺中的CD4(+)CD25(+) T细胞进行表型分析。使用酶联免疫吸附测定法（ELISA）测量支气管肺泡灌洗液（BALF）中白细胞介素-4（IL-4）、白细胞介素-5（IL-5）、白细胞介素-10（IL-10）、干扰素-γ（IFN-γ）和白细胞介素-13的浓度。来自肺或脾组织的NTregs和iTregs可逆转气道高反应性至少4周。然而，抗PD-1抗体的给药阻断了治疗效果。给Tregs受体小鼠施用抗PD-1抗体可显著降低细胞毒性T淋巴细胞抗原-4的表达，肺CD4(+)CD25(+) T细胞中叉头翼状转录因子框3（Foxp3）mRNA转录本的浓度较低。这些小鼠的BALF中IL-4、IL-5和IL-13的浓度显著更高，但BALF中IL-10的水平显著降低。未使用抗PD-1抗体的过继治疗受体在肺CD4(+)CD25(+) T细胞中表现出高水平的细胞毒性T淋巴细胞相关抗原4（CTLA-4）表达和Foxp3转录本，BALF中IL-4、IL-5和IL-13的浓度显著降低，BALF中IL-10的浓度大幅增加。这些数据表明，Tregs对气道高反应性和气道炎症的逆转部分是由PD-1介导的，因为其他共刺激分子（如诱导性共刺激分子[ICOS]或CTLA-4）已被证明在Treg介导的抑制中起作用。
