Department of Pathophysiology and Immunology, 49552National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.
Clinic of Connective Tissue Diseases, 49552National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.
Cell Transplant. 2020 Jan-Dec;29:963689720945682. doi: 10.1177/0963689720945682.
Activated T lymphocytes play an important role in the pathogenesis of rheumatic diseases (RD). Mesenchymal stem cells (MSCs) possess immunoregulatory activities but such functions of MSCs from bone marrow of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and ankylosing spondylitis (AS) patients are impaired. Adipose tissue-derived MSCs (ASCs) are an optional pool of therapeutically useful MSCs, but biology of these cells in RD is poorly known. This study aimed at investigating the effect of ASCs from RD patients and healthy donors (HD) on the expression of the key T-cell activation markers.
ASCs were isolated from subcutaneous abdominal fat from SLE ( = 16), SSc ( = 18), and AS ( = 16) patients, while five human ASCs lines from HD were used as a control. Untreated and cytokine (tumor necrosis factor α + interferon γ)-treated ASCs were co-cultured with allogenic, mitogen (phytohemagglutinin)-stimulated peripheral blood mononuclear cells (PBMCs) or purified anti-CD3/CD28-activated CD4 T lymphocytes. Contacting and noncontacting ASCs-PBMCs co-cultures were performed. RD/ASCs were analyzed in co-cultures with both allogeneic and autologous PBMCs. Flow cytometry analysis was used to evaluate expression of CD25, HLA-DR, and CD69 molecules on CD4 and CD8 cells.
In co-cultures with allogeneic, activated CD4 T cells and PBMCs, HD/ASCs and RD/ASCs downregulated CD25 and HLA-DR, while upregulated CD69 molecules expression on both CD4 and CD8 cells with comparable potency. This modulatory effect was similar in contacting and noncontacting co-cultures. RD/ASCs exerted weaker inhibitory effect on CD25 expression on autologous than allogeneic CD4 and CD8 T cells.
RD/ASCs retain normal capability to regulate expression of activation markers on allogeneic T cells. Both HD/ASCs and RD/ASCs exert this effect independently of their activation status, mostly through the indirect pathway and soluble factors. However, autologous CD4 and CD8 T cells are partially resistant to RD/ASCs inhibition of CD25 expression, suggesting weaker control of T-cell activation .
活化的 T 淋巴细胞在风湿性疾病（RD）的发病机制中发挥重要作用。间充质干细胞（MSCs）具有免疫调节活性，但红斑狼疮（SLE）、系统性硬化症（SSc）和强直性脊柱炎（AS）患者骨髓来源的 MSCs 功能受损。脂肪组织来源的间充质干细胞（ASCs）是一种有治疗用途的 MSC 可选来源，但这些细胞在 RD 中的生物学特性知之甚少。本研究旨在探讨 RD 患者和健康供体（HD）来源的 ASC 对关键 T 细胞激活标志物表达的影响。
从 SLE（n=16）、SSc（n=18）和 AS（n=16）患者的皮下腹部脂肪中分离 ASC，同时使用 5 个人源 ASC 系作为对照。未经处理和细胞因子（肿瘤坏死因子 α+干扰素 γ）处理的 ASC 与同种异体、丝裂原（植物血凝素）刺激的外周血单个核细胞（PBMCs）或纯化的抗 CD3/CD28 激活的 CD4 T 淋巴细胞共培养。进行接触和非接触 ASC-PBMC 共培养。在与同种异体和自体 PBMC 共培养中分析 RD/ASC。流式细胞术分析用于评估 CD4 和 CD8 细胞上 CD25、HLA-DR 和 CD69 分子的表达。
在与同种异体、激活的 CD4 T 细胞和 PBMCs 共培养中，HD/ASC 和 RD/ASC 下调 CD25 和 HLA-DR 的表达，同时上调 CD4 和 CD8 细胞上 CD69 分子的表达，具有相当的效力。这种调节作用在接触和非接触共培养中相似。RD/ASC 对自体 CD4 和 CD8 T 细胞的 CD25 表达的抑制作用弱于同种异体。
RD/ASC 保持正常调节同种异体 T 细胞激活标志物表达的能力。HD/ASC 和 RD/ASC 均独立于其激活状态通过间接途径和可溶性因子发挥此作用。然而，自体 CD4 和 CD8 T 细胞对 RD/ASC 抑制 CD25 表达的作用部分抵抗，表明对 T 细胞激活的控制较弱。
