肝内浸润 T 细胞 CD28 表达缺失导致原发性硬化性胆管炎发病机制。
Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis.
机构信息
Centre for Liver Research and National Institute for Health Research Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom.
Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom.
出版信息
Gastroenterology. 2014 Jul;147(1):221-232.e7. doi: 10.1053/j.gastro.2014.04.003. Epub 2014 Apr 12.
BACKGROUND & AIMS: T-cell-mediated biliary injury is a feature of primary sclerosing cholangitis (PSC). We studied the roles of CD28(-) T cells in PSC and their regulation by vitamin D.
METHODS
Peripheral and liver-infiltrating mononuclear cells were isolated from blood or fresh liver tissue. We analyzed numbers, phenotypes, functions, and localization patterns of CD28(-) T cells, along with their ability to activate biliary epithelial cells. We measured levels of tumor necrosis factor (TNF)α in liver tissues from patients with PSC and the effects of exposure to active vitamin D (1,25[OH]2D3) on expression of CD28.
RESULTS
A significantly greater proportion of CD4(+) and CD8(+) T cells that infiltrated liver tissues of patients with PSC were CD28(-), compared with control liver tissue (CD4(+): 30.3% vs 2.5%, P < .0001; and CD8(+): 68.5% vs 31.9%, P < .05). The mean percentage of CD4(+)CD28(-) T cells in liver tissues from patients with PSC was significantly higher than from patients with primary biliary cirrhosis or nonalcoholic steatohepatitis (P < .05). CD28(-) T cells were activated CD69(+)CD45RA(-) C-C chemokine receptor (CCR)7(-) effector memory and perforin(+) granzyme B(+) cytotoxic cells, which express CD11a, CX3CR1, C-X3-C motif receptor 6 (CXCR6), and CCR10-consistent with their infiltration of liver and localization around bile ducts. Compared with CD28(+) T cells, activated CD28(-) T cells produced significantly higher levels of interferon γ and TNFα (P < .05), and induced up-regulation of intercellular cell adhesion molecule-1, HLA-DR, and CD40 by primary epithelial cells (3.6-fold, 1.5-fold, and 1.2-fold, respectively). Liver tissue from patients with PSC contained high levels of TNFα; TNFα down-regulated the expression of CD28 by T cells in vitro (P < .01); this effect was prevented by administration of 1,25(OH)2D3 (P < .05).
CONCLUSIONS
Inflammatory CD28(-) T cells accumulate in livers of patients with PSC and localize around bile ducts. The TNFα-rich microenvironment of this tissue promotes inflammation; these effects are reversed by vitamin D in vitro.
背景与目的
T 细胞介导的胆管损伤是原发性硬化性胆管炎（PSC）的特征。我们研究了 CD28(-)T 细胞在 PSC 中的作用及其受维生素 D 的调节。
方法
从血液或新鲜肝组织中分离外周和肝浸润的单核细胞。我们分析了 CD28(-)T 细胞的数量、表型、功能和定位模式，以及它们激活胆管上皮细胞的能力。我们测量了 PSC 患者肝组织中肿瘤坏死因子（TNF）α的水平，以及暴露于活性维生素 D（1,25[OH]2D3）对 CD28 表达的影响。
结果
与对照肝组织相比，浸润 PSC 患者肝脏的 CD4(+)和 CD8(+)T 细胞中 CD28(-)T 细胞的比例显著更高（CD4(+)：30.3% vs 2.5%，P<0.0001；CD8(+)：68.5% vs 31.9%，P<0.05）。PSC 患者肝组织中 CD4(+)CD28(-)T 细胞的平均百分比明显高于原发性胆汁性肝硬化或非酒精性脂肪性肝炎患者（P<0.05）。CD28(-)T 细胞是激活的 CD69(+)CD45RA(-)C-C 趋化因子受体（CCR）7(-)效应记忆和穿孔素（+）颗粒酶 B（+）细胞毒性细胞，表达 CD11a、CX3CR1、C-X3-C 基序受体 6（CXCR6）和 CCR10-与它们在肝脏中的浸润和胆管周围的定位一致。与 CD28(+)T 细胞相比，激活的 CD28(-)T 细胞产生的干扰素 γ和 TNFα 水平显著更高（P<0.05），并诱导原发性上皮细胞上调细胞间黏附分子-1、HLA-DR 和 CD40（分别为 3.6 倍、1.5 倍和 1.2 倍）。PSC 患者的肝组织中含有高水平的 TNFα；TNFα 在体外下调 T 细胞中 CD28 的表达（P<0.01）；这种作用被 1,25(OH)2D3 的给药所阻止（P<0.05）。
结论
在 PSC 患者的肝脏中积累了炎症性 CD28(-)T 细胞，并定位于胆管周围。该组织富含 TNFα 的微环境促进了炎症；这些影响在体外被维生素 D 逆转。
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