Distinct robes of CTLA-4 and TGF-β in CD4+CD25+ regulatory T cell function
Distinct robes of CTLA-4 and TGF-β in CD4+CD25+ regulatory T cell function
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DOI：
10.1002/eji.200425143
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发表时间：
2004-11-01
影响因子：
5.4
通讯作者：
Bluestone, JA
中科院分区：
文献类型：
--
作者：
Tang, QZ;Boden, EK;Bluestone, JA
CTLA-4和TGF-β都与CD 4（+）CD 25（+）调节性T细胞（Treg）的抑制有关。在这项研究中，检查了CTLA-4和TGF-β在Treg功能中的关系。阻断野生型Treg上的CTLA-4在体外消除了它们的抑制活性，而中和TGF-β没有影响，支持CTLA-4在Treg介导的体外抑制中的TGF-β非依赖性作用。在CTLA-4缺陷小鼠中，Treg发育和稳态正常。此外，来自CTLA-4基因敲除小鼠的Treg在体外表现出不受损害的抑制活性。这些CTLA-4缺陷型Treg表达的抑制性细胞因子IL-10和TGF-β水平增加，并且由CTLA-4（-/-）Treg介导的体外抑制通过中和TGF-β而显著降低，表明CTLA-4缺陷型Treg通过CTLA-4非依赖性产生TGF-β而形成代偿性抑制机制。总之，这些数据表明CTLA-4通过两种不同的机制调节Treg功能，一种在Treg的功能发育期间，另一种在效应物阶段期间，此时需要CTLA-4信号传导途径进行抑制。这些结果有助于解释文献中的矛盾，并支持功能不同的Treg的存在。
Both CTLA-4 and TGF-beta have been implicated in suppression by CD4(+)CD25(+) regulatory T cells (Treg). In this study, the relationship between CTLA-4 and TGF-beta in Treg function was examined. Blocking CTLA-4 on wild-type Treg abrogated their suppressive activity in vitro, whereas neutralizing TGF-beta had no effect, supporting a TGF-beta-independent role for CTLA-4 in Treg-mediated suppression in vitro. In CTLA-4-deficient mice, Treg development and homeostasis was normal. Moreover, Treg from CTLA-4-cleficient mice exhibited uncompromised suppressive activity in vitro. These CTLA-4-cleficient Treg expressed increased levels of the suppressive cytokines IL-10 and TGF-P, and in vitro suppression mediated by CTLA4(-/-)Treg was markedly reduced by neutralizing TGF-beta, suggesting that CTLA-4-deficientTreg develop a compensatory suppressive mechanism through CTLA-4-independent production of TGF-beta. Together, these data suggest that CTLA-4 regulates Treg function by two distinct mechanisms, one during functional development of Treg and the other during the effector phase, when the CTLA-4 signaling pathway is required for suppression. These results help explain contradictions in the literature and support the existence of functionally distinct Treg.