A CD8 T cell/indoleamine 2,3-dioxygenase axis is required for mesenchymal stem cell suppression of human systemic lupus erythematosus.
A CD8 T cell/indoleamine 2,3-dioxygenase axis is required for mesenchymal stem cell suppression of human systemic lupus erythematosus.
复制标题
DOI：
10.1002/art.38674
复制
发表时间：
2014-08
影响因子：
13.3
通讯作者：
Sun, Lingyun
中科院分区：
文献类型：
--
作者：
Wang, Dandan;Feng, Xuebing;Lu, Lin;Konkel, Joanne E.;Zhang, Huayong;Chen, Zhiyong;Li, Xia;Gao, Xiang;Lu, Liwei;Shi, Songtao;Chen, Wanjun;Sun, Lingyun
同种异体间充质干细胞（MSCs）在人类自身免疫性疾病如系统性红斑狼疮（SLE）中表现出治疗作用，但其潜在机制仍不清楚。本研究的目的是探讨同种异体间充质干细胞如何介导狼疮患者的免疫抑制。测定同种异体脐带来源的间充质干细胞（UC-MSCs）对T细胞增殖的抑制作用。MSC功能分子刺激与外周血单个核细胞从健康对照组和SLE患者，并通过实时聚合酶链反应。使用微珠纯化CD 4+和CD 8 + T细胞以刺激MSC，以确定MSC的细胞因子表达，并进一步确定哪种细胞亚群或哪种分子参与MSC介导的T细胞增殖的抑制。对相关信号通路进行了评估。我们测定了狼疮患者UC-MSC移植前后血清细胞因子的水平。同种异体UC-MSCs通过分泌大量吲哚胺2，3-双加氧酶（IDO）抑制狼疮患者的T细胞增殖。我们进一步发现，主要由狼疮CD 8 + T细胞产生的干扰素-γ（IFNγ）是增强同种异体MSC中IDO活性的关键因子，并且它与IFNGR 1/JAK-2/STAT信号通路相关。有趣的是，来自活动性狼疮患者的骨髓来源的MSC表现出响应于IFNγ和同种异体CD 8 + T细胞刺激的IDO产生缺陷。同种异体UC-MSC移植后，狼疮患者血清IDO活性升高。我们发现了一个以前未被认识到的CD 8 + T细胞/IFNγ/IDO轴，它介导了同种异体MSC在狼疮患者中的治疗效果。
Allogeneic mesenchymal stem cells (MSCs) exhibit therapeutic effects in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain largely unknown. The aim of this study was to investigate how allogeneic MSCs mediate immunosuppression in lupus patients. The effects of allogeneic umbilical cord–derived MSCs (UC-MSCs) on inhibition of T cell proliferation were determined. MSC functional molecules were stimulated with peripheral blood mononuclear cells from healthy controls and SLE patients and examined by real-time polymerase chain reaction. CD4+ and CD8+ T cells were purified using microbeads to stimulate MSCs in order to determine cytokine expression by MSCs and to further determine which cell subset(s) or which molecule(s) is involved in inhibition of MSC–mediated T cell proliferation. The related signaling pathways were assessed. We determined levels of serum cytokines in lupus patients before and after UC-MSC transplantation. Allogeneic UC-MSCs suppressed T cell proliferation in lupus patients by secreting large amounts of indoleamine 2,3-dioxygenase (IDO). We further found that interferon-γ (IFNγ), which is produced predominantly by lupus CD8+ T cells, is the key factor that enhances IDO activity in allogeneic MSCs and that it is associated with IFNGR1/JAK-2/STAT signaling pathways. Intriguingly, bone marrow–derived MSCs from patients with active lupus demonstrated defective IDO production in response to IFNγ and allogeneic CD8+ T cell stimulation. After allogeneic UC-MSC transplantation, serum IDO activity increased in lupus patients. We found a previously unrecognized CD8+ T cell/IFNγ/IDO axis that mediates the therapeutic effects of allogeneic MSCs in lupus patients.
登录
查看更多内容
影响因子：
20.3
作者：
Meisel, R;Zibert, A;Dilloo, D
通讯作者：
Dilloo, D
影响因子：
4.4
作者：
Harigai, Masayoshi;Kawamoto, Manabu;Miyasaka, Nobuyuki
通讯作者：
Miyasaka, Nobuyuki
影响因子：
20.3
作者：
Aggarwal, S;Pittenger, MF
通讯作者：
Pittenger, MF
影响因子：
8.6
作者：
Gu, Fei;Molano, Ivan;Gilkeson, Gary S.
通讯作者：
Gilkeson, Gary S.
DOI：
10.1038/nrrheum.2010.60
发表时间：
2010-06
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
--