Mitochondrial Deacetylase SIRT3 Plays an Important Role in Donor T Cell Responses after Experimental Allogeneic Hematopoietic Transplantation.
Mitochondrial Deacetylase SIRT3 Plays an Important Role in Donor T Cell Responses after Experimental Allogeneic Hematopoietic Transplantation.
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DOI：
10.4049/jimmunol.1800148
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发表时间：
2018-12-01
期刊：
影响因子：
--
通讯作者：
Reddy P
中科院分区：
文献类型：
--
作者：
Toubai T;Tamaki H;Peltier DC;Rossi C;Oravecz-Wilson K;Liu C;Zajac C;Wu J;Sun Y;Fujiwara H;Henig I;Kim S;Lombard DB;Reddy P
异基因造血干细胞移植（allo-HCT）通过其移植物抗肿瘤（GVT）效应是一种治疗多种血液恶性肿瘤的有效方法。然而，GVT与allo-HCT后有害的移植物抗宿主病（GVHD）有关。GVT和GVHD都需要同种异体T细胞应答，这是一个能量昂贵的过程，会导致氧化应激。Sirtuin 3（SIRT 3）是一种线粒体组蛋白脱乙酰酶（HDAC），通过抑制活性氧（ROS）在细胞内发挥重要作用。非线粒体类HDAC调节T细胞应答;但线粒体HDAC，特别是SIRT 3，在allo-HCT后对供体T细胞应答的作用仍然未知。在此，我们报告了SIRT 3缺陷型（SIRT 3-/-）供体T细胞在多种临床相关小鼠模型中引起GVHD严重程度降低。同种异体SIRT 3-/- T细胞的GVHD保护作用与其活化的减少、CXCR 3表达的减少相关，并且对细胞因子分泌或细胞毒性功能没有显著影响。有趣的是，SIRT 3-/- T细胞的GVHD保护作用与ROS产生的减少相关，这与SIRT 3缺陷对其他细胞/组织中ROS产生的影响相反，并且可能是其缺陷活化的结果。值得注意的是，胃肠道（GI）中GVHD的减少与移植物抗肿瘤（GVT）效应的显著降低无关。总的来说，这些数据揭示了SIRT 3活性促进同种异体供体T细胞应答和ROS产生而不改变T细胞细胞因子或细胞溶解功能，并将SIRT 3鉴定为供体T细胞上的新靶标以改善allo-HCT后的结果。
Allogeneic stem cell transplantation (allo-HCT) through its graft-versus-tumor (GVT) effects is a curative therapy against many hematological malignancies. However, GVT is linked to harmful graft-versus-host disease (GVHD) after allo-HCT. Both GVT and GVHD require allogeneic T cell responses, which is an energetically costly process that causes oxidative stress. Sirtuin 3 (SIRT3), a mitochondrial histone deacetylases (HDAC), plays an important role in cellular processes through inhibition of reactive oxygen species (ROS). Non-mitochondrial class of HDACs regulate T cell responses; but the role of mitochondrial HDACs, specifically SIRT3, on donor T cell responses after allo-HCT remain unknown. Herein we report that SIRT3 deficient (SIRT3-/-) donor T cells cause reduced GVHD severity in multiple clinically relevant murine models. The GVHD protective effect of allogeneic SIRT3-/- T cells was associated with a reduction in their activation, reduced CXCR3 expression, and no significant impact on cytokine secretion or cytotoxic functions. Intriguingly, the GVHD protective effect of SIRT3-/- T cells was associated with a reduction in ROS production which is contrary to the effect of SIRT3 deficiency on ROS production in other cells/tissues and likely a consequence of their deficient activation. Notably the reduction in GVHD in the gastrointestinal (GI) tract was not associated with a substantial reduction in the graft-versus-tumor (GVT) effect. Collectively these data reveal that SIRT3 activity promotes allogeneic donor T cell responses and ROS production without altering T cell cytokine or cytolytic functions and identify SIRT3 as a novel target on donor T cells to improve outcomes after allo-HCT.
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影响因子：
8.8
作者：
Brown K;Xie S;Qiu X;Mohrin M;Shin J;Liu Y;Zhang D;Scadden DT;Chen D
通讯作者：
Chen D
DOI：
10.1016/s1470-2045(13)70512-6
发表时间：
2014-01
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Choi SW;Braun T;Chang L;Ferrara JL;Pawarode A;Magenau JM;Hou G;Beumer JH;Levine JE;Goldstein S;Couriel DR;Stockerl-Goldstein K;Krijanovski OI;Kitko C;Yanik GA;Lehmann MH;Tawara I;Sun Y;Paczesny S;Mapara MY;Dinarello CA;DiPersio JF;Reddy P
通讯作者：
Reddy P
SIRT3在饮食限制期间促进尿素周期和脂肪酸氧化。
影响因子：
16
作者：
Hallows WC;Yu W;Smith BC;Devries MK;Ellinger JJ;Someya S;Shortreed MR;Prolla T;Markley JL;Smith LM;Zhao S;Guan KL;Denu JM
通讯作者：
Denu JM
影响因子：
3.7
作者：
Buler M;Aatsinki SM;Izzi V;Hakkola J
通讯作者：
Hakkola J
影响因子：
32.4
作者：
Groom JR;Richmond J;Murooka TT;Sorensen EW;Sung JH;Bankert K;von Andrian UH;Moon JJ;Mempel TR;Luster AD
通讯作者：
Luster AD