Cell contact, prostaglandin E2 and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25Highforkhead box P3+ regulatory T cells
Cell contact, prostaglandin E2 and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25Highforkhead box P3+ regulatory T cells
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DOI：
10.1111/j.1365-2249.2009.03874.x
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发表时间：
2009-04-01
影响因子：
4.6
通讯作者：
Mahon, B. P.
中科院分区：
文献类型：
--
作者：
English, K.;Ryan, J. M.;Mahon, B. P.
成人间充质干细胞(MSC)可以分化为多种细胞类型，是再生医学的候选细胞疗法。令人惊讶的是，这些细胞还显示出多种强大的免疫调节能力，包括同种异体抑制，使异基因细胞治疗成为可能。使用纯化的CD4(+)细胞和具有良好特性的成人骨髓来源的MSC，研究了同种异体人MSC诱导调节性T细胞的确切机制。同种异体MSC可诱导CD4(+)T细胞表达叉头盒P3(FoxP3)(+)和CD25(+)基因和蛋白。这种现象需要MSC和纯化的T细胞直接接触，尽管MSC在未分离的单个核细胞群体中诱导FoxP3表达不需要细胞接触。此外，通过使用拮抗剂和中和抗体，MSC衍生的前列腺素和转化生长因子β1在诱导CD4(+)CD25(+)FoxP3(+)T细胞中具有非多余的作用。经MSC共培养后，纯化的CD4(+)CD25(+)T细胞表达转化生长因子-β1，并能抑制混合淋巴细胞反应中同种异体抗原诱导的增殖反应。这些数据阐明了人类MSC介导的同种异体抑制的机制，支持了调节性T细胞诱导的一系列过程，包括MSC与CD4(+)细胞的直接接触，随后前列腺素E-2和转化生长因子-β1的表达。总体而言，这项研究为正在进行的涉及异基因骨髓间充质干细胞的临床研究提供了合理的基础。
Adult human mesenchymal stromal or stem cells (MSC) can differentiate into a variety of cell types and are candidate cellular therapeutics in regenerative medicine. Surprisingly, these cells also display multiple potent immunomodulatory capabilities, including allosuppression, making allogeneic cell therapy a possibility. The exact mechanisms involved in regulatory T cell induction by allogeneic human MSC was examined, using purified CD4(+) populations and well-characterized bone marrow-derived adult human MSC. Allogeneic MSC were shown to induce forkhead box P3 (FoxP3)(+) and CD25(+) mRNA and protein expression in CD4(+) T cells. This phenomenon required direct contact between MSC and purified T cells, although cell contact was not required for MSC induction of FoxP3 expression in an unseparated mononuclear cell population. In addition, through use of antagonists and neutralizing antibodies, MSC-derived prostaglandins and transforming growth factor (TGF)-beta 1 were shown to have a non-redundant role in the induction of CD4(+)CD25(+)FoxP3(+) T cells. Purified CD4(+)CD25(+) T cells induced by MSC co-culture expressed TGF-beta 1 and were able to suppress alloantigen-driven proliferative responses in mixed lymphocyte reaction. These data clarify the mechanisms of human MSC-mediated allosuppression, supporting a sequential process of regulatory T cell induction involving direct MSC contact with CD4(+) cells followed by both prostaglandin E-2 and TGF-beta 1 expression. Overall, this study provides a rational basis for ongoing clinical studies involving allogeneic MSC.