MFG-E8 Is Critical for Embryonic Stem Cell-Mediated T Cell Immunomodulation.
MFG-E8 Is Critical for Embryonic Stem Cell-Mediated T Cell Immunomodulation.
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DOI：
10.1016/j.stemcr.2015.09.005
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发表时间：
2015-11-10
影响因子：
5.9
通讯作者：
Wang L
中科院分区：
文献类型：
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作者：
Tan Y;AlKhamees B;Jia D;Li L;Couture JF;Figeys D;Jinushi M;Wang L
与未分化胚胎干细胞（ESC）的低免疫原性相关的分子和机制仍然知之甚少。在这里，我们提供的证据表明，牛奶脂肪球表皮生长因子8（MFG-E8）是一个重要的介质，在这种现象，并直接抑制T细胞免疫反应。MFG-E8在未分化的ESC中富集，但在分化的ESC中减少。MFG-E8在ESC中的上调增加了未分化和分化的ESC跨越主要组织相容性复合物屏障的成功植入。MFG-E8抑制T细胞活化/增殖并抑制Th 1、Th 2和Th 17亚群，同时增加调节性T细胞亚群。中和MFG-E8基本上消除了这些作用，而将重组MFG-E8添加到分化的胚胎干细胞中则恢复了免疫抑制。此外，我们提供了MFG-E8通过α3/5βV整联蛋白受体抑制PKCθ磷酸化来抑制T细胞活化和调节T细胞极化的证据。我们的研究结果提供了一种促进移植接受的方法。MFG-E8富含未分化但减少分化的ESC MFG-E8促进ESC衍生组织的同种异体植入穿过MHC屏障ESC产生的MFG-E8抑制Th 1/Th 2/Th 17，同时促进调节性T细胞MFG-E8通过抑制PKCθ磷酸化调节T细胞极化牛奶脂肪球表皮生长因子8（MFG-E8）最初在乳腺上皮细胞中鉴定。Wang，Jinushi及其同事发现MFG-E8富含未分化的ESC，并通过抑制PKCθ磷酸化来调节T细胞反应。MFG-E8的上调促进非自体ESC及其衍生物成功植入穿过MHC屏障。
The molecules and mechanisms pertinent to the low immunogenicity of undifferentiated embryonic stem cells (ESCs) remain poorly understood. Here, we provide evidence that milk fat globule epidermal growth factor 8 (MFG-E8) is a vital mediator in this phenomenon and directly suppresses T cell immune responses. MFG-E8 is enriched in undifferentiated ESCs but diminished in differentiated ESCs. Upregulation of MFG-E8 in ESCs increases the successful engraftment of both undifferentiated and differentiated ESCs across major histocompatibility complex barriers. MFG-E8 suppresses T cell activation/proliferation and inhibits Th1, Th2, and Th17 subpopulations while increasing regulatory T cell subsets. Neutralizing MFG-E8 substantially abrogates these effects, whereas addition of recombinant MFG-E8 to differentiated ESCs restores immunosuppression. Furthermore, we provide the evidence that MFG-E8 suppresses T cell activation and regulates T cell polarization by inhibiting PKCθ phosphorylation through the α3/5βV integrin receptor. Our findings offer an approach to facilitate transplantation acceptance. MFG-E8 is enriched in undifferentiated but diminished in differentiated ESCs MFG-E8 promotes allogeneic engraftment of ESC-derived tissues across the MHC barrier ESC-produced MFG-E8 inhibits Th1/Th2/Th17 while promoting regulatory T cells MFG-E8 modulates T cell polarization via inhibiting PKCθ phosphorylation Milk fat globule epidermal growth factor 8 (MFG-E8) is originally identified in mammary gland epithelial cells. Wang, Jinushi, and colleagues find that MFG-E8 is enriched in undifferentiated ESCs and modulates T cell responses via inhibition of PKCθ phosphorylation. Upregulation of MFG-E8 promotes successful engraftment of non-self ESCs and their derivatives across the MHC barrier.