CTLA4-Ig Restores Rejection of MHC Class-II Mismatched Allografts by Disabling IL-2-Expanded Regulatory T Cells
CTLA4-Ig Restores Rejection of MHC Class-II Mismatched Allografts by Disabling IL-2-Expanded Regulatory T Cells
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DOI：
10.1111/j.1600-6143.2012.04184.x
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发表时间：
2012-09-01
影响因子：
8.8
通讯作者：
Le Moine, A.
中科院分区：
文献类型：
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作者：
Charbonnier, L. -M.;Vokaer, B.;Le Moine, A.
同种异体移植物的接受和耐受可以通过不同的方法来实现，包括通过CD 28依赖性共刺激阻断抑制效应T细胞应答和诱导外周调节性T细胞（T细胞）。观察到TclO依赖于CD 28依赖性信号进行发育和外周扩增，这提出了CTLA 4-IG施用对耐受诱导产生反作用结果的有趣的可能性。我们已经研究了CTLA 4-IG对Treg介导的耐受性诱导的可能的负面影响，使用单一MHC II类错配皮肤移植物的小鼠模型，其中通过短期施用IL-2/抗IL-2复合物实现长期接受。发现CTLA 4-IG治疗消除了该模型中的Treg依赖性接受，恢复了皮肤同种异体移植物排斥和Th 1同种异体反应性。CTLA 4-IG抑制IL-2驱动的Treg扩增，特别是防止具有有效抑制能力的ICOS+ Treg的发生。恢复CD 28信号传导足以抵消CTLA 4-IG对Treg扩增和功能的有害作用，这与共刺激阻断通过限制必需的CD 28依赖性信号的递送来抑制Treg扩增和功能的假设一致。因此，在设计基于共刺激阻断的耐受方案时，应考虑到调节性T细胞功能的抑制。
Allograft acceptance and tolerance can be achieved by different approaches including inhibition of effector T cell responses through CD28-dependent costimulatory blockade and induction of peripheral regulatory T cells (Tregs). The observation that Tregs rely upon CD28-dependent signals for development and peripheral expansion, raises the intriguing possibility of a counterproductive consequence of CTLA4-Ig administration on tolerance induction. We have investigated the possible negative effect of CTLA4-Ig on Treg-mediated tolerance induction using a mouse model of single MHC class II-mismatched skin grafts in which long-term acceptance was achieved by short-term administration of IL-2/anti-IL-2 complex. CTLA4-Ig treatment was found to abolish Treg-dependent acceptance in this model, restoring skin allograft rejection and Th1 alloreactivity. CTLA4-Ig inhibited IL-2-driven Treg expansion, and prevented in particular the occurrence of ICOS+ Tregs endowed with potent suppressive capacities. Restoring CD28 signaling was sufficient to counteract the deleterious effect of CTLA4-Ig on Treg expansion and functionality, in keeping with the hypothesis that costimulatory blockade inhibits Treg expansion and function by limiting the delivery of essential CD28-dependent signals. Inhibition of regulatory T cell function should therefore be taken into account when designing tolerance protocols based on costimulatory blockade.