CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion
CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion
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DOI：
10.1182/blood-2007-11-125435
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发表时间：
2008-08-15
期刊：
影响因子：
20.3
通讯作者：
Fong, Lawrence
中科院分区：
文献类型：
--
作者：
Kavanagh, Brian;O'Brien, Shaun;Fong, Lawrence
细胞毒性T淋巴细胞相关抗原4（CTLA4）向活化的T细胞传递抑制信号。CTLA4在调节性CD4（+）T细胞（Tregs）上组成性表达，但其在这些细胞中的作用仍不清楚。CTLA4阻断已被证明可诱导抗肿瘤免疫。在本研究中，我们检测了抗CTLA4抗体对癌症患者内源性CD4 + T细胞的影响。我们发现CTLA4阻断不仅使活化的效应CD4 + T细胞数量增加，也使CD4 + FoxP3（+）Tregs数量增加。尽管这种影响呈剂量依赖性，但在较低抗体剂量下CD4 + FoxP3 +调节性T细胞即可扩增。相反，效应T细胞的扩增仅在所研究的最高剂量水平下才能观察到。此外，这些扩增的CD4 + FoxP3 +调节性T细胞在治疗过程中被诱导增殖并具有抑制功能。我们的结果表明，抗CTLA4抗体治疗在体内不会耗竭人CD4 + FoxP3 + Tregs，而是可能通过活化效应T细胞来介导其作用。我们的结果还提示，CTLA4可能类似于其在效应T细胞上的作用一样抑制Treg增殖。本研究在http://www.clinicaltrials.gov/ct2/show/NCT00064129注册，注册号为NCT00064129。
Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) delivers inhibitory signals to activated T cells. CTLA4 is constitutively expressed on regulatory CD4(+) T cells (Tregs), but its role in these cells remains unclear. CTLA4 blockade has been shown to induce antitumor immunity. In this study, we examined the effects of anti-CTLA4 antibody on the endogenous CD4+ T cells in cancer patients. We show that CTLA4 blockade induces an increase not only in the number of activated effector CD4+ T cells, but also in the number of CD4+ FoxP3(+) Tregs. Although the effects were dose-dependent, CD4+ FoxP3+ regulatory T cells could be expanded at lower antibody doses. In contrast, expansion of effector T cells was seen only at the highest dose level studied. Moreover, these expanded CD4+ FoxP3+ regulatory T cells are induced to proliferate with treatment and possess suppressor function. Our results demonstrate that treatment with anti-CTLA4 antibody does not deplete human CD4+ FoxP3+ Tregs in vivo, but rather may mediate its effects through the activation of effector T cells. Our results also suggest that CTLA4 may inhibit Treg proliferation similar to its role on effector T cells. This study is registered at http://www.clinicaltrials.gov/ct2/show/NCT00064129, registry number NCT00064129.