Contrasting effects of cyclosporine and rapamycin in de novo generation of alloantigen-specific regulatory T cells
Contrasting effects of cyclosporine and rapamycin in de novo generation of alloantigen-specific regulatory T cells
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DOI：
10.1111/j.1600-6143.2007.01842.x
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发表时间：
2007-07-01
影响因子：
8.8
通讯作者：
Strom, T. B.
中科院分区：
文献类型：
--
作者：
Gao, W.;Lu, Y.;Strom, T. B.
T细胞介导的应答结果是免疫还是耐受，关键取决于细胞毒性T细胞与调节性T细胞（T-reg细胞）的平衡。在对主要组织相容性复合体（MHC）不相容的同种异体移植物建立稳定耐受时，通常需要通过细胞凋亡减少大量异常的供体反应性细胞毒性T效应细胞（T-eff细胞）。环孢素（CsA）阻断T-eff细胞的激活诱导的细胞死亡（AICD），不利于通过共刺激阻断诱导耐受，而雷帕霉素（RPM）保留AICD，并增强共刺激阻断产生耐受的潜力。虽然CsA和RPM在影响活化的具有移植物破坏性的T-eff细胞凋亡方面的差异是明显的，但它们对具有移植物保护作用的T-reg细胞的影响仍然不清楚。此外，尚不清楚耐受方案是否促进初始外周T细胞转化为同种抗原特异性T-reg细胞以保护移植物。在此，我们利用T-reg标记物Foxp3的报告小鼠表明，RPM促进同种抗原特异性T-reg细胞的从头转化，而CsA完全抑制这一过程。在转移后，体内转化的T-reg细胞能有效抑制供体皮肤移植物的排斥反应，但对第三方皮肤移植物无此作用。因此，RPM和CsA对T-eff细胞和T-reg细胞的不同作用有利于在将攻击性同种免疫转变为保护性同种免疫的平衡中使用RPM。
The outcome of T-cell-mediated responses, immunity or tolerance, critically depends on the balance of cytopathic versus regulatory T (T-reg) cells. In the creation of stable tolerance to MHC incompatible allografts, reducing the unusually large mass of donor-reactive cytopathic T effector (T-eff) cells via apoptosis is often required. Cyclosporine (CsA) blocks activation-induced cell death (AICD) of T-eff cells, and is detrimental to tolerance induction by costimulation blockade, whereas Rapamycin (RPM) preserves AICD, and augments the potential of costimulation blockade to create tolerance. While differences between CsA and RPM in influencing apoptosis of activated graft-destructive T-eff cells are apparent, their effects on graft-protective T-reg cells remain enigmatic. Moreover, it is unclear whether tolerizing regimens foster conversion of naive peripheral T cells into alloantigen-specific T-reg cells for graft protection. Here we show, using reporter mice for T-reg marker Foxp3, that RPM promotes de novo conversion of alloantigen-specific T-reg cells, whereas CsA completely inhibits this process. Upon transfer, in vivo converted T-reg cells potently suppress the rejection of donor but not third party skin grafts. Thus, the differential effects of RPM and CsA on T-eff and T-reg cells favor the use of RPM in shifting the balance of aggressive to protective type alloimmunity.