CCL2 deficient mesenchymal stem cells fail to establish long-lasting contact with T cells and no longer ameliorate lupus symptoms.
CCL2 deficient mesenchymal stem cells fail to establish long-lasting contact with T cells and no longer ameliorate lupus symptoms.
复制标题
CCL2缺乏间充质干细胞无法与T细胞建立长期接触，并且不再改善狼疮症状。
DOI：
10.1038/srep41258
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发表时间：
2017-01-24
影响因子：
4.6
通讯作者：
Han SB
中科院分区：
文献类型：
--
作者：
Lee HK;Kim HS;Kim JS;Kim YG;Park KH;Lee JH;Kim KH;Chang IY;Bae SC;Kim Y;Hong JT;Kehrl JH;Han SB
系统性红斑狼疮(SLE)是一种以自身抗体产生为特征的多器官自身免疫性疾病。间充质干细胞(MSCs)通过靶向T细胞来改善SLE症状，但其疗效机制尚不完全清楚。在这项研究中，我们表明，转移人MSCs可以提高MRL.Faslpr小鼠的存活率，减少肾脏中T细胞的侵袭，并减少T细胞细胞因子的表达。在体外，同种异体小鼠MSCs抑制MRL.Faslpr T细胞的增殖和细胞因子的产生。时间推移成像显示，MSCs招募了MRL.Faslpr T细胞，通过以CCL2依赖的方式增强T细胞VCAM-1的表达，建立了长期的细胞接触。相反，CCL2缺陷的MSCs没有诱导T细胞迁移和VCAM-1的表达，导致细胞与细胞之间的接触不足。因此，CCL2缺陷的MSCs不会抑制T细胞产生干扰素-γ，并且在转移后不再延长MRL.Faslpr小鼠的存活时间。综上所述，我们的成像研究表明，CCL2能够实现充分抑制自身反应性T细胞所需的长时间的MSC-T细胞相互作用，并有助于了解MSCs如何改善狼疮易患MRL.Faslpr小鼠的症状。
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by autoantibody production. Mesenchymal stem cells (MSCs) ameliorate SLE symptoms by targeting T cells, whereas the mechanisms of their efficacy remain incompletely understood. In this study, we show that transfer of human MSCs increased MRL.Faslpr mouse survival, decreased T cell infiltration in the kidneys, and reduced T cell cytokine expression. In vitro, allogeneic mouse MSCs inhibited MRL.Faslpr T cell proliferation and cytokine production. Time-lapse imaging revealed that MSCs recruited MRL.Faslpr T cells establishing long-lasting cellular contacts by enhancing T cell VCAM-1 expression in a CCL2-dependent manner. In contrast, CCL2 deficient MSCs did not induce T cell migration and VCAM-1 expression, resulting in insufficient cell-cell contact. Consequently, CCL2 deficient MSCs did not inhibit IFN-γ production by T cells and upon transfer no longer prolonged survival of MRL.Faslpr mice. Taken together, our imaging study demonstrates that CCL2 enables the prolonged MSC–T cell interactions needed for sufficient suppression of autoreactive T cells and helps to understand how MSCs ameliorate symptoms in lupus-prone MRL.Faslpr mice.