Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor.
Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor.
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介导同种异体移植耐受性的FOXP3+ T调节细胞的募集取决于CCR4趋化因子受体。
DOI：
10.1084/jem.20041709
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发表时间：
2005-04-04
影响因子：
15.3
通讯作者：
Hancock, WW
中科院分区：
文献类型：
--
作者：
Lee, I;Wang, LQ;Wells, AD;Dorf, ME;Ozkaynak, E;Hancock, WW
尽管某些趋化因子及其受体引导T细胞的稳态再循环，而其他趋化因子及其受体则促进活化T细胞募集至炎症部位，但人们对第三种功能的机制知之甚少，即Foxp 3+调节性T（T reg）细胞迁移至它们保持无反应性的部位。我们研究了CD 154单克隆抗体（mAb）联合供体特异性输血（DST）耐受的受者心脏移植物中T细胞的募集情况。实时聚合酶链反应显示，耐受受体的移植物内Foxp 3水平比排斥同种异体移植物或与其他疗法相关的同种异体移植物高100倍，诱导延长生存期，但不耐受。Foxp 3+细胞对于耐受性是必不可少的，因为移植前胸腺切除术或移植物周围CD 25+细胞耗竭会阻止长期存活，就像CD 154/DST治疗后功能良好的同种异体移植物中的CD 25 mAb治疗一样。对多种趋化因子途径的分析表明，耐受伴随着CCR 4及其配体之一巨噬细胞衍生趋化因子（CCL 22）的移植物内上调，并且在CCR 4 −/−受体中不能实现耐受诱导。我们的结论是，Foxp 3的表达是特异性上调小鼠同种异体移植物显示供体特异性耐受，招募Foxp 3表达的T reg细胞的同种异体移植物组织依赖于趋化因子受体，CCR 4，并且，在这种招聘的情况下，耐受性策略，如CD 154单克隆抗体治疗是无效的。
Although certain chemokines and their receptors guide homeostatic recirculation of T cells and others promote recruitment of activated T cells to inflammatory sites, little is known of the mechanisms underlying a third function, migration of Foxp3+ regulatory T (T reg) cells to sites where they maintain unresponsiveness. We studied how T reg cells are recruited to cardiac allografts in recipients tolerized with CD154 monoclonal antibody (mAb) plus donor-specific transfusion (DST). Real-time polymerase chain reaction showed that intragraft Foxp3 levels in tolerized recipients were ∼100-fold higher than rejecting allografts or allografts associated with other therapies inducing prolonged survival but not tolerance. Foxp3+ cells were essential for tolerance because pretransplant thymectomy or peritransplant depletion of CD25+ cells prevented long-term survival, as did CD25 mAb therapy in well-functioning allografts after CD154/DST therapy. Analysis of multiple chemokine pathways showed that tolerance was accompanied by intragraft up-regulation of CCR4 and one of its ligands, macrophage-derived chemokine (CCL22), and that tolerance induction could not be achieved in CCR4−/− recipients. We conclude that Foxp3 expression is specifically up-regulated within allografts of mice displaying donor-specific tolerance, that recruitment of Foxp3-expressing T reg cells to an allograft tissue is dependent on the chemokine receptor, CCR4, and that, in the absence of such recruitment, tolerizing strategies such as CD154 mAb therapy are ineffectual.
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DOI：
10.1084/jem.194.6.847
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Iellem A;Mariani M;Lang R;Recalde H;Panina-Bordignon P;Sinigaglia F;D'Ambrosio D
通讯作者：
D'Ambrosio D
影响因子：
6.2
作者：
Jarvinen, LZ;Blazar, BR;Noelle, RJ
通讯作者：
Noelle, RJ
影响因子：
82.9
作者：
Hancock, WW;Buelow, R;Turka, LA
通讯作者：
Turka, LA
影响因子：
4.4
作者：
Nakamura, K;Kitani, A;Strober, W
通讯作者：
Strober, W
影响因子：
4.4
作者：
Cobbold, SP;Castejon, R;Waldmann, H
通讯作者：
Waldmann, H