Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants
Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants
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DOI：
10.4049/jimmunol.172.10.6003
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发表时间：
2004-05-15
影响因子：
4.4
通讯作者：
Waldmann, H
中科院分区：
文献类型：
--
作者：
Cobbold, SP;Castejon, R;Waldmann, H
在非耗竭性CD 4 + CD 8或CD 154 mAb的覆盖下进行移植，可诱导小鼠移植耐受。这种耐受性是供体抗原特异性的，并依赖于CD 4（+）调节性T细胞的群体，迄今为止，在其特异性，起源和表型方面仍然定义不清。用抗CD 4单克隆抗体阻断Ag特异性体外反应，可使来自单特异性雌性TCR转基因小鼠的T细胞表达高水平的foxP 3 mRNA，这些T细胞可对抗由H-2 E（k）呈递的雄性Ag Dby。foxP 3诱导依赖于TGF-β。非消耗性抗CD 4 mAb也能够在这种单特异性TCR转基因小鼠中诱导体内耐受，这也依赖于TGF-β。与常规小鼠一样，获得性耐受是显性的，使得幼稚单特异性T细胞不能超越耐受。来自耐受小鼠的脾T细胞在对Ag的反应中正常增殖，并分泌IFN-γ和一些IL-4，与经历原发性或继发性移植物排斥的对照小鼠相似。在长期耐受受者的耐受皮肤移植物中发现高水平的foxP 3 mRNA和糖皮质激素诱导的TNFR超家族成员18（GITR）（+）CD 25（+）T细胞。这些数据表明，在CD 4 Ab阻断后维持移植耐受的调节性T细胞可以通过TGF-β依赖性机制从头诱导，并在耐受的移植物中积累。
Transplantation tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This tolerance is donor Ag specific and depends on a population of CD4(+) regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2E(k), to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-beta. The nondepleting anti-CD4 mAb was also able to induce tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-beta. As in conventional mice, acquired tolerance was dominant, such that naive monospecific T cells were not able to override tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-gamma and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)(+) CD25(+) T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining transplantation tolerance after CD4 Ab blockade can be induced de novo through a TGF-beta-dependent mechanism, and come to accumulate in tolerated grafts.