Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma.
Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma.
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DOI：
10.1158/0008-5472.can-05-3773
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发表时间：
2006-03-15
期刊：
影响因子：
11.2
通讯作者：
Sampson, JH
中科院分区：
文献类型：
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作者：
Fecci, PE;Mitchell, DA;Sampson, JH
免疫抑制常与恶性肿瘤有关，在恶性胶质瘤患者中尤为严重。无反应性和T（H）2细胞因子产生的反作用转变是这些患者中长期公认的T细胞缺陷，其病因学在> 30年内一直难以捉摸。我们发现恶性胶质瘤患者的CD 4（+）T细胞和CD 4（+）CD 25（+）FOXP 3（+）CD 45 RO（+）T细胞（T-T细胞）的绝对计数显著减少，但T-T细胞通常代表剩余的CD 4部分的增加。这种增加的T-reg分数，尽管计数减少，但与体外受损患者T细胞反应性的特征表现相关并足以引起这种特征表现。此外，Treg去除根除了T细胞增殖缺陷并逆转了TH 2细胞因子的转变，使恶性胶质瘤患者的T细胞在体外以与正常健康对照相当的水平发挥功能。这种恢复的免疫功能可以给予生理抗神经胶质瘤活性许可，因为在体内，T-reg耗竭证明允许在已建立的颅内神经胶质瘤的鼠模型中的自发肿瘤排斥。这些发现极大地改变了我们对恶性胶质瘤患者细胞免疫功能低下的理解，并促进了T-T细胞在中枢神经系统中促进肿瘤免疫逃避的作用。
Immunosuppression is frequently associated with malignancy and is particularly severe in patients with malignant glioma. Anergy and counterproductive shifts toward T(H)2 cytokine production are long-recognized T-cell defects in these patients whose etiology has remained elusive for > 30 years. We show here that absolute counts of both CD4(+) T cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+) T cells (T-regs) are greatly diminished in patients with malignant glioma, but T-regs frequently represent an increased fraction of the remaining CD4 compartment. This increased T-reg fraction, despite reduced counts, correlates with and is sufficient to elicit the characteristic manifestations of impaired patient T-cell responsiveness in vitro. Furthermore, Treg removal eradicates T-cell proliferative defects and reverses TH2 cytokine shifts, allowing T cells from patients with malignant glioma to function in vitro at levels equivalent to those of normal, healthy controls. Such restored immune function may give license to physiologic antiglioma activity, as in vivo, T-reg depletion proves permissive for spontaneous tumor rejection in a murine model of established intracranial glioma. These findings dramatically alter our understanding of depressed cellular immune function in patients with malignant glioma and advance a role for T-regs in facilitating tumor immune evasion in the central nervous system.