Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production
Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production
复制标题
DOI：
10.1182/blood-2006-01-0329
复制
发表时间：
2006-07-01
期刊：
影响因子：
20.3
通讯作者：
Negrin, Robert S.
中科院分区：
文献类型：
--
作者：
Zeiser, Robert;Nguyen, Vu. H.;Negrin, Robert S.
CD4(+)CD25(+)调节性T (Treg)细胞控制免疫耐受和抗肿瘤免疫反应。因此，免疫抑制药物对 Treg 功能的体内修饰对移植生物学、自身免疫和疫苗接种策略具有广泛的影响。体内生物发光成像表明，在主要组织相容性复合体错配骨髓移植后，用 Treg 细胞治疗的动物中，供体来源的荧光素酶标记的常规 T 细胞的早期增殖减少。将 Treg 细胞与环孢素 A (CSA) 结合使用，但不与雷帕霉素 (RAPA) 或吗替麦考酚酯 (MMF) 结合使用，可以通过 T 细胞增殖增加、移植物抗宿主病 (GVHD) 严重程度和存活率降低来抑制 Treg 功能。该群体中 Treg 和 FoxP3 表达的扩增与 CSA 结合最低，表明钙依赖磷酸酶依赖性白细胞介素 2 (IL-2) 的产生对于体内 Treg 细胞至关重要。 CSA暴露后Treg细胞的功能缺陷可以被外源性IL-2逆转。此外，Treg 与 RAPA 组合保留了针对白血病细胞的移植物抗肿瘤 (GVT) 效应功能。我们的数据表明，RAPA 和 MMF 而不是 CSA 在 GVHD 等病理免疫反应中保留了 Treg 细胞的功能，而不会削弱 GVT 效应。
CD4(+)CD25(+) regulatory T (Treg) cells control immunologic tolerance and antitumor immune responses. Therefore, in vivo modification of Treg function by immuno-suppressant drugs has broad implications for transplantation biology, autoimmunity, and vaccination strategies. In vivo bioluminescence imaging demonstrated reduced early proliferation of donor-derived luciferase-labeled conventional T cells in animals treated with Treg cells after major histocompatibility complex mismatch bone marrow transplantation. Combining Treg cells with cyclosporine A (CSA), but not rapamycin (RAPA) or mycophenolate mofetil (MMF), suppressed Treg function assessed by increased T-cell proliferation, graft-versus-host disease (GVHD) severity, and reduced survival. Expansion of Treg and FoxP3 expression within this population was lowest in conjunction with CSA, suggesting that calcineurin-dependent interleukin 2 (IL-2) production is critically required for Treg cells in vivo. The functional defect of Treg cells after CSA exposure could be reversed by exogenous IL-2. Further, the Treg plus RAPA combination preserved graft-versus-tumor (GVT) effector function against leukemia cells. Our data indicate that RAPA and MMF rather than CSA preserve function of Treg cells in pathologic immune responses such as GVHD without weakening the GVT effect.