Qiu Chen, Yang Lanlan, Liu Siqi, Zhang Chuanhui, Zhang Qian, Jin Zhenjing
Digestive Disease Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, Jilin Province 130041, People's Republic of China.
Digestive Disease Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, Jilin Province 130041, People's Republic of China.
Int Immunopharmacol. 2023 Jan 24:109751. doi: 10.1016/j.intimp.2023.109751.
The phenotype shift in regulatory T cells (Tregs) contributes to immunopathogenesis of autoimmune diseases. The current study was aimed to investigate the regulatory function of interleukin-35 (IL-35) to T helper 22 (Th22) cell phenotype shift in Tregs in primary biliary cholangitis (PBC). Fifty-five PBC patients and twenty-four controls were enrolled. CD4CD25CD127 Tregs and Th22 cells were investigated by flow cytometry. Forkhead box P3 (FoxP3) and aryl hydrocarbon receptor (AhR) mRNA levels were assessed by real-time polymerase chain reaction. Plasma IL-10 and IL-22 levels were measured by ELISA. Purified Tregs were stimulated with exogenous IL-35, and were co-cultured with autologous CD4CD25 T cells. Cellular proliferation and cytokine production was measured. Purified Tregs were also cultured into Th22 condition in the presence or absence of exogenous IL-35, and Th22 phenotype were assessed. PBC patients had lower levels of Treg percentage, FoxP3 mRNA, and plasma IL-10, while had higher levels of Th22 proportion, AhR mRNA, and plasma IL-22. Tregs from PBC patients showed reduced immunosuppressive activity, which presented as increased cellular proliferation, interferon-γ production and decreased IL-35/IL-10 secretion in co-culture system. Tregs shifted into Th22 phenotype in PBC patients with elevated CCR4, CCR6, and CCR10 expression as well as increased IL-22 production. IL-35 not only enhanced inhibitory function of Tregs but also suppressed phenotype shift of Tregs into Th22 phenotype in PBC patients. This process was accompanied by elevation of IL-10 and transforming growth factor-β1 secretion by Tregs from PBC patients. The present data suggested that reduced IL-35 might be insufficient to maintain Tregs function and phenotype shift from Tregs into Th22 phenotype in PBC patients.
调节性T细胞（Tregs）的表型转变有助于自身免疫性疾病的免疫发病机制。当前研究旨在探讨白细胞介素-35（IL-35）对原发性胆汁性胆管炎（PBC）患者Tregs中辅助性T细胞22（Th22）细胞表型转变的调节功能。纳入了55例PBC患者和24例对照。通过流式细胞术检测CD4⁺CD25⁺CD127⁻ Tregs和Th22细胞。通过实时聚合酶链反应评估叉头框P3（FoxP3）和芳烃受体（AhR）mRNA水平。通过酶联免疫吸附测定法检测血浆IL-10和IL-22水平。用外源性IL-35刺激纯化的Tregs，并与自体CD4⁺CD25⁻ T细胞共培养。检测细胞增殖和细胞因子产生情况。纯化的Tregs也在有或无外源性IL-35的情况下培养成Th22条件，并评估Th22表型。PBC患者的Treg百分比、FoxP3 mRNA和血浆IL-10水平较低，而Th22比例、AhR mRNA和血浆IL-22水平较高。PBC患者的Tregs显示出免疫抑制活性降低，在共培养系统中表现为细胞增殖增加、干扰素-γ产生增加以及IL-35/IL-IO分泌减少。PBC患者中Tregs转变为Th22表型，其CCR4、CCR6和CCR10表达升高以及IL-22产生增加。IL-35不仅增强了PBC患者Tregs的抑制功能，还抑制了Tregs向Th22表型的转变。这一过程伴随着PBC患者Tregs分泌的IL-10和转化生长因子-β1升高。目前的数据表明，IL-35减少可能不足以维持PBC患者Tregs的功能以及Tregs向Th22表型的转变。
