CCR5 expression levels influence NFAT translocation, IL-2 production, and subsequent signaling events during T lymphocyte activation.
CCR5 expression levels influence NFAT translocation, IL-2 production, and subsequent signaling events during T lymphocyte activation.
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DOI：
10.4049/jimmunol.182.1.171
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Ahuja SK
中科院分区：
文献类型：
--
作者：
Camargo JF;Quinones MP;Mummidi S;Srinivas S;Gaitan AA;Begum K;Jimenez F;VanCompernolle S;Unutmaz D;Ahuja SS;Ahuja SK
HIV-1的主要共受体CCR 5的配体共刺激T淋巴细胞活化。然而，CCR 5表达对T细胞应答的全部影响仍然未知。在这里，我们表明，与CCR 5 +/+相比，CCR 5 −/−小鼠的T细胞分泌的IL-2量较低，并且在缺乏CCR 5表达的人类（CCR 5-Δ32/Δ32纯合子）中观察到类似的表型，以及在CCR 5表达基因完整的人类T细胞中进行CCR 5的Ab介导阻断后。相反，人T细胞中CCR 5的过表达导致IL-2产生增加。CCR 5表面水平与IL-2蛋白和mRNA丰度正相关，表明CCR 5影响IL-2基因调节。通过CCR 5的信号传导导致T细胞中的NFAT反式激活，其被针对CCR 5激动剂的Ab阻断，表明CCR 5与影响IL-2表达的下游途径之间的联系。此外，缺乏CCR 5的鼠T细胞在活化后具有降低的核内NFAT水平。因此，CCR 5表达也促进IL-2依赖性事件，包括CD 25表达、STAT 5磷酸化和T细胞增殖。因此，我们认为，通过影响NFAT介导的途径，调节IL-2的生产和IL-2依赖的事件，CCR 5可能在T细胞反应中发挥关键作用。在雅阁与我们以前的推论，从遗传流行病学研究，这种CCR 5依赖的反应可能构成了一个病毒进入独立的机制，CCR 5可能会影响艾滋病毒-艾滋病的发病机制。
Ligands of CCR5, the major coreceptor of HIV-1, costimulate T lymphocyte activation. However, the full impact of CCR5 expression on T cell responses remains unknown. Here, we show that compared with CCR5+/+, T cells from CCR5−/− mice secrete lower amounts of IL-2, and a similar phenotype is observed in humans who lack CCR5 expression (CCR5-Δ32/Δ32 homozygotes) as well as after Ab-mediated blockade of CCR5 in human T cells genetically intact for CCR5 expression. Conversely, overexpression of CCR5 in human T cells results in enhanced IL-2 production. CCR5 surface levels correlate positively with IL-2 protein and mRNA abundance, suggesting that CCR5 affects IL-2 gene regulation. Signaling via CCR5 resulted in NFAT transactivation in T cells that was blocked by Abs against CCR5 agonists, suggesting a link between CCR5 and downstream pathways that influence IL-2 expression. Furthermore, murine T cells lacking CCR5 had reduced levels of intranuclear NFAT following activation. Accordingly, CCR5 expression also promoted IL-2-dependent events, including CD25 expression, STAT5 phosphorylation, and T cell proliferation. We therefore suggest that by influencing a NFAT-mediated pathway that regulates IL-2 production and IL-2-dependent events, CCR5 may play a critical role in T cell responses. In accord with our prior inferences from genetic-epidemiologic studies, such CCR5-dependent responses might constitute a viral entry-independent mechanism by which CCR5 may influence HIV-AIDS pathogenesis.
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影响因子：
7.7
作者：
Abdi, R;Smith, RN;Sayegh, MH
通讯作者：
Sayegh, MH
影响因子：
6.2
作者：
Akashi, S;Sho, M;Nakajima, Y
通讯作者：
Nakajima, Y
影响因子：
3.3
作者：
Blanpain, C;Vanderwinden, JM;Mack, M
通讯作者：
Mack, M
影响因子：
15.3
作者：
Bonecchi, R;Bianchi, G;Bordignon, P P;D'Ambrosio, D;Lang, R;Borsatti, A;Sozzani, S;Allavena, P;Gray, P A;Mantovani, A;Sinigaglia, F
通讯作者：
Sinigaglia, F
影响因子：
168.9
作者：
Fischereder, M;Luckow, B;Schlöndorff, D
通讯作者：
Schlöndorff, D