Requirements for Growth and IL-10 Expression of Highly Purified Human T Regulatory Cells
Requirements for Growth and IL-10 Expression of Highly Purified Human T Regulatory Cells
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DOI：
10.1007/s10875-012-9701-4
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发表时间：
2012-10-01
影响因子：
9.1
通讯作者：
Verbsky, James W.
中科院分区：
文献类型：
--
作者：
Bonacci, Benedetta;Edwards, Brandon;Verbsky, James W.
人类调节性T细胞（T - R细胞）有用于治疗多种免疫介导疾病的潜力，但这些细胞的无反应性表型使其难以在体外扩增。我们已经研究了高纯度人类T - R细胞生长和细胞因子表达的需求，并将这些发现与这些细胞的信号转导事件相关联。我们证明，即使在高剂量白细胞介素 - 2（IL - 2）存在的情况下，这些细胞也不会增殖或分泌白细胞介素 - 10（IL - 10）。用一种超激动性抗CD28抗体（克隆9.3）和白细胞介素 - 2刺激可部分逆转增殖缺陷，这与这些细胞中钙动员缺陷的逆转相关。树突状细胞可有效促进T - R细胞增殖，在这些条件下，T - R细胞的增殖能力与常规CD4淋巴细胞相当。阻断转化生长因子 - β（TGF - β）活性可消除这些细胞中白细胞介素 - 10的表达，而添加转化生长因子 - β则会导致白细胞介素 - 10产生。这些数据表明，即使在高剂量白细胞介素 - 2存在的情况下，高纯度的T - R细胞群也是无反应性的。此外，抗原呈递细胞提供适当的共刺激以克服T - R细胞的无反应性表型，并且在这些条件下它们对白细胞介素 - 2高度敏感。此外，这些数据首次表明转化生长因子 - β对于使人类T - R细胞表达白细胞介素 - 10至关重要。
Human regulatory T cells (T-R) cells have potential for the treatment of a variety of immune mediated diseases but the anergic phenotype of these cells makes them difficult to expand in vitro. We have examined the requirements for growth and cytokine expression from highly purified human T-R cells, and correlated these findings with the signal transduction events of these cells. We demonstrate that these cells do not proliferate or secrete IL-10 even in the presence of high doses of IL-2. Stimulation with a superagonistic anti-CD28 antibody (clone 9.3) and IL-2 partially reversed the proliferative defect, and this correlated with reversal of the defective calcium mobilization in these cells. Dendritic cells were effective at promoting T-R cell proliferation, and under these conditions the proliferative capacity of T-R cells was comparable to conventional CD4 lymphocytes. Blocking TGF-beta activity abrogated IL-10 expression from these cells, while addition of TGF-beta resulted in IL-10 production. These data demonstrate that highly purified populations of T-R cells are anergic even in the presence of high doses of IL-2. Furthermore, antigen presenting cells provide proper co-stimulation to overcome the anergic phenotype of T-R cells, and under these conditions they are highly sensitive to IL-2. In addition, these data demonstrate for the first time that TGF-beta is critical to enable human T-R cells to express IL-10.