CTLA-4 blockade decreases TGF-β, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques
CTLA-4 blockade decreases TGF-β, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques
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DOI：
10.1182/blood-2006-04-010637
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发表时间：
2006-12-01
期刊：
影响因子：
20.3
通讯作者：
Franchini, Genoveffa
中科院分区：
文献类型：
--
作者：
Hryniewicz, Anna;Boasso, Adriano;Franchini, Genoveffa
调节性T细胞（T-reg）是CD25(+)CD4(+) T细胞的一个亚群，组成性表达高水平的细胞毒性T淋巴细胞抗原-4 （CTLA-4）并抑制T细胞活化和效应功能。感染HIV-1的个体和感染猴免疫缺陷病毒（SIVmac251）的猕猴的组织中Treg细胞增加。在HIV-1感染中，T-reg细胞可以发挥不同的作用：它们可以通过减少免疫激活来限制病毒复制，或者通过抑制病毒特异性免疫反应来增加病毒复制。因此，阻断T-reg功能在HIW/SIV中的结果需要实证检验。在这里，我们证明CD25(+) T细胞抑制siv感染猕猴血液和淋巴结培养的T细胞中的病毒特异性T细胞反应。我们利用抗CTLA-4人抗体MDX-010研究了阻断CTLA-4对接受抗逆转录病毒治疗（ART）的siv感染猕猴的影响。CTLA-4阻断降低了组织中色氨酸消耗酶IDO的表达和抑制性细胞因子转化生长因子- β (tgf - β)的水平。CTLA-4阻断与淋巴结中病毒RNA水平的降低以及siv特异性CD4（+）和CD8(+) T细胞效应功能的增加有关。因此，在SIV感染的猕猴中，减弱T，g功能没有有害的病毒学效应，可能为补充ART和治疗性疫苗接种治疗HIV-1感染提供了一种有价值的方法。
Regulatory T (T-reg) cells are a subset of CD25(+)CD4(+) T cells that constitutively express high levels of cytotoxic T lymphocyte antigen-4 (CTLA-4) and suppress T-cell activation and effector functions. Treg cells are increased in tissues of individuals infected with HIV-1 and macaques infected with simian immunodeficiency virus (SIVmac251). In HIV-1 infections T-reg cells could exert contrasting effects: they may limit viral replication by decreasing immune activation, or they may increase viral replication by suppressing virus-specific immune response. Thus, the out-come of blocking T-reg function in HIW/SIV should be empirically tested. Here, we demonstrate that CD25(+) T cells inhibit virus-specific T-cell responses in cultured T cells from blood and lymph nodes of SIV-infected macaques. We investigated the impact of CTLA-4 blockade using the anti-CTLA-4 human antibody MDX-010 in SIV-infected macaques treated with antiretroviral therapy (ART). CTLA-4 blockade decreased expression of the tryptophan-depleting enzyme IDO and the level of the suppressive cytokine transforming growth factor-beta (TGF-beta) in tissues. CTLA-4 blockade was associated with decreased viral RNA levels in lymph nodes and an increase in the effector function of both SIV-specific CD4(+) and CD8(+) T cells. Therefore, blunting T,g function in macaques infected with SIV did not have detrimental virologic effects and may provide a valuable approach to complement ART and therapeutic vaccination in the treatment of HIV-1 infection.