STAT5 polarization promotes iTregs and suppresses human T-cell alloresponses while preserving CTL capacity
STAT5 polarization promotes iTregs and suppresses human T-cell alloresponses while preserving CTL capacity
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DOI：
10.1189/jlb.0313154
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发表时间：
2014-02-01
影响因子：
5.5
通讯作者：
Anasetti, Claudio
中科院分区：
文献类型：
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作者：
Betts, Brian C.;Veerapathran, Anandharaman;Anasetti, Claudio
选择性STAT 3抑制控制人T细胞同种异体反应性，同时允许STAT 5介导的免疫调节和效应功能。同种异体反应性对来自同种异体供体的器官移植或HCT的结果产生负面影响。标准的药理学免疫抑制损害T细胞功能，并危及有益的T细胞重建。小鼠移植模型已经显示，STAT 3在同种异体反应性T细胞中高度表达，并且可以是治疗靶向的。然而，STAT 3中和在人类同种异体反应性中的影响和作用仍有待阐明。在这项研究中，S3 I-201，一种选择性的小分子STAT 3抑制剂，抑制人DC-同种异体致敏的T细胞增殖和废除Th 17反应。STAT 3阻断显著增强了有效的iT细胞的扩增，并允许CD 8（+）细胞溶解效应子功能。从机制上讲，S3 I-201使STAT磷酸化的比率极化，有利于STAT 5超过STAT 3，并且还在iTcR中实现了显著程度的Foxp 3去甲基化。相反，用CAS 285986-31-4选择性损伤STAT 5磷酸化显著降低iTlR。STAT 3代表用于实现对人类同种异体反应的控制的相关靶标，其中其抑制促进STAT 5介导的iTreg生长和功能。
Selective STAT3 inhibition controls human T cell alloreactivity, while permitting STAT5-mediated immune regulatory and effector functions. Alloreactivity negatively influences outcomes of organ transplantation or HCT from allogeneic donors. Standard pharmacologic immune suppression impairs T-cell function and jeopardizes the beneficial reconstitution of Tregs. Murine transplantation models have shown that STAT3 is highly expressed in alloreactive T cells and may be therapeutically targeted. The influence and effects of STAT3 neutralization in human alloreactivity, however, remain to be elucidated. In this study, S3I-201, a selective small-molecule inhibitor of STAT3, suppressed human DC-allosensitized T-cell proliferation and abrogated Th17 responses. STAT3 blockade significantly enhanced the expansion of potent iTregs and permitted CD8(+) cytolytic effector function. Mechanistically, S3I-201 polarized the ratio of STAT phosphorylation in favor of STAT5 over STAT3 and also achieved a significant degree of Foxp3 demethylation among the iTregs. Conversely, selective impairment of STAT5 phosphorylation with CAS 285986-31-4 markedly reduced iTregs. STAT3 represents a relevant target for achieving control over human alloresponses, where its suppression facilitates STAT5-mediated iTreg growth and function.