Expression of Programmed Death-Ligand 1 by Human Colonic CD90(+) Stromal Cells Differs Between Ulcerative Colitis and Crohn's Disease and Determines Their Capacity to Suppress Th1 Cells.
Expression of Programmed Death-Ligand 1 by Human Colonic CD90(+) Stromal Cells Differs Between Ulcerative Colitis and Crohn's Disease and Determines Their Capacity to Suppress Th1 Cells.
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DOI：
10.3389/fimmu.2018.01125
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发表时间：
2018
影响因子：
7.3
通讯作者：
Pinchuk IV
中科院分区：
文献类型：
--
作者：
Beswick EJ;Grim C;Singh A;Aguirre JE;Tafoya M;Qiu S;Rogler G;McKee R;Samedi V;Ma TY;Reyes VE;Powell DW;Pinchuk IV
在炎症性肠病(IBD)中，程序性细胞死亡蛋白1(PD-1)及其配体在辅助性T细胞免疫反应失调中的作用尚不清楚。最近，一个新的概念出现了，CD90+结肠(Myo)成纤维细胞(CMF)，也被称为基质细胞，作为免疫抑制细胞，是急、慢性炎症的关键调节因子之一。本研究的目的是确定炎性结肠黏膜中PD-1配体的水平是否发生了变化，并验证了IBD-CMF介导的PD-1配体相关免疫抑制的变化是促进Th1 细胞应答失调的机制。对来自克罗恩病(CD)、溃疡性结肠炎(UC)和健康人(N)的组织和细胞进行了原位、体外和培养研究。与非炎症匹配组织样本、CD和健康对照组相比，炎症UC结肠粘膜中的程序性死亡配体1(PD-L1)显著增加。UC-CMF是导致PD-L1表达增强的主要细胞群之一。而CD-CMF组PD-L1表达降低。与CD-CMF和N-CMF相比，UC-CMF对CD_3/CD_(28)活化的CD_4+T细胞表达IL-2、Th1转录因子Tbet和干扰素-γ有更强的抑制作用，且这一过程是PD-L1依赖的。分化的Th1型 细胞与UC-CMF共培养时也有类似的观察结果。相反，CD-CMF显示抑制Th1型 细胞活性的能力降低，在CD-CMF中加入重组PD-L1Fc：T细胞共培养部分恢复了对Th1型反应的抑制。我们提出的证据表明，PD-L1表达增加抑制了UC中Th1型 细胞的活性。相反，CD中PD-L1表达的缺失有助于CD中Th1炎症环境的持续存在。我们的数据表明IBD患者炎症的结肠黏膜中Th1反应的失调是由粘膜间充质间质细胞室中PD-L1表达的变化所促进的。
The role of programmed cell death protein 1 (PD-1) and its ligands in the dysregulation of T helper immune responses observed in the inflammatory bowel disease (IBD) is unclear. Recently, a novel concept emerged that CD90+ colonic (myo)fibroblasts (CMFs), also known as stromal cells, act as immunosuppressors, and are among the key regulators of acute and chronic inflammation. The objective of this study was to determine if the level of the PD-1 ligands is changed in the IBD inflamed colonic mucosa and to test the hypothesis that changes in IBD-CMF-mediated PD-1 ligand-linked immunosuppression is a mechanism promoting the dysregulation of Th1 cell responses. Tissues and cells derived from Crohn’s disease (CD), ulcerative colitis (UC), and healthy individuals (N) were studied in situ, ex vivo, and in culture. A significant increase in programmed death-ligand 1 (PD-L1) was observed in the inflamed UC colonic mucosa when compared to the non-inflamed matched tissue samples, CD, and healthy controls. UC-CMFs were among the major populations in the colonic mucosa contributing to the enhanced PD-L1 expression. In contrast, PD-L1 expression was decreased in CD-CMFs. When compared to CD-CMFs and N-CMFs, UC-CMFs demonstrated stronger suppression of IL-2, Th1 transcriptional factor Tbet, and IFN-γ expression by CD3/CD28-activated CD4+ T cells, and this process was PD-L1 dependent. Similar observations were made when differentiated Th1 cells were cocultured with UC-CMFs. In contrast, CD-CMFs showed reduced capacity to suppress Th1 cell activity and addition of recombinant PD-L1 Fc to CD-CMF:T cell cocultures partially restored the suppression of the Th1 type responses. We present evidence showing that increased PD-L1 expression suppresses Th1 cell activity in UC. In contrast, loss of PD-L1 expression observed in CD contributes to the persistence of the Th1 inflammatory milieu in CD. Our data suggest that dysregulation of the Th1 responses in the inflamed colonic mucosa of IBD patients is promoted by the alterations in PD-L1 expression in the mucosal mesenchymal stromal cell compartment.