HIV-1 binding to CD4 on CD4+CD25+ regulatory T cells enhances their suppressive function and induces them to home to, and accumulate in, peripheral and mucosal lymphoid tissues: an additional mechanism of immunosuppression.
HIV-1 binding to CD4 on CD4+CD25+ regulatory T cells enhances their suppressive function and induces them to home to, and accumulate in, peripheral and mucosal lymphoid tissues: an additional mechanism of immunosuppression.
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DOI：
10.1093/intimm/dxn146
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发表时间：
2009-03
影响因子：
4.4
通讯作者：
Jiaxiang Ji;M. Cloyd
中科院分区：
文献类型：
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作者：
Jiaxiang Ji;M. Cloyd
已证明许多慢性感染的建立和持续存在取决于 CD4+CD25+ 调节性 T (Treg) 细胞对抗微生物免疫反应活力的抑制。在 HIV 感染者中，Treg 细胞抑制 HIV 特异性和一般 CD4+ 和 CD8+ T 细胞反应。病毒感染期间 CD4+CD25+ Treg 细胞功能的增强可能是由宿主衍生的促炎分子介导的，也可能是直接由病毒感染或结合介导的。我们通过将来自健康供体的人纯化 CD4+CD25+ T 细胞在体外暴露于 HIV-1 并评估其 Treg 相关功能标记谱和抑制活性，检查了 HIV 对与 CD4+CD25+ Treg 细胞结合的影响。我们发现，HIV-1 结合使它们的抑制活性增加 2 至 5 倍，同时 Treg 相关功能标记物 sCTLA-4、糖皮质激素诱导的肿瘤坏死因子受体和 FoxP3 的表达增强。此外，HIV-1结合延长了CD4+CD25+Treg细胞的存活时间，并上调归巢受体CD62L和整合素α4β7的表达，这反过来又会导致Treg细胞更快地迁移到发生抗HIV免疫反应的外周淋巴结和粘膜淋巴组织。重要的是，暴露于 HIV 的 CD4+CD25+ Treg 细胞不像 HIV-1 结合后的其他静息 CD4+ 细胞那样容易受到归巢诱导的细胞凋亡的影响。我们发现 CD4+CD25+ Treg 细胞通过 HIV gp120 与 CD4 分子的相互作用直接对 HIV-1 本身做出反应。总的来说，我们的研究结果解释了一种机制，该机制导致 HIV 患者的淋巴和粘膜组织中强化的 Treg 细胞异常积累，从而导致免疫反应受损，这将极大地帮助 HIV 持续存在。
The establishment and persistence of many chronic infections have been demonstrated to depend on restraint of the vigor of the anti-microbial immune responses by CD4+CD25+ regulatory T (Treg) cells. In HIV-infected individuals, Treg cells suppress both HIV-specific and general CD4+ and CD8+ T cell responses. Increases of CD4+CD25+ Treg cell function during viral infections might be mediated by host-derived pro-inflammatory molecules or directly by viral infection or binding. We examined the effect HIV has upon binding to CD4+CD25+ Treg cells by exposing human purified CD4+CD25+ T cells from healthy donors to HIV-1 in vitro and assessing their Treg-associated functional marker profile and suppressive activities. We found that HIV-1 binding increased their suppressor activities by 2- to 5-fold, which was accompanied by enhanced expression of Treg-associated functional markers sCTLA-4, glucocorticoid-induced tumor necrosis factor receptor and FoxP3. Moreover, HIV-1 binding extended the survival of CD4+CD25+ Treg cells and up-regulated the expression of homing receptors CD62L and integrin alpha4beta7, which in turn would result in Treg cells migrating more rapidly to the peripheral lymph nodes and mucosal lymphoid tissues where anti-HIV immune responses are occurring. Importantly, CD4+CD25+ Treg cells exposed to HIV were not susceptible to homing-induced apoptosis like are other resting CD4+ cells following HIV-1 binding. We show that CD4+CD25+ Treg cells respond directly to HIV-1 itself through HIV gp120 interactions with CD4 molecules. Collectively, our findings explain a mechanism that contributes to the abnormal accumulation of intensified Treg cells in lymphoid and mucosal tissues in HIV patients, resulting in impairment of immune responses which would greatly help HIV persistence.