Human Herpesvirus 8 (HHV8) sequentially shapes the NK cell repertoire during the course of asymptomatic infection and Kaposi sarcoma.
Human Herpesvirus 8 (HHV8) sequentially shapes the NK cell repertoire during the course of asymptomatic infection and Kaposi sarcoma.
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DOI：
10.1371/journal.ppat.1002486
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发表时间：
2012-01
期刊：
影响因子：
6.7
通讯作者：
Caillat-Zucman S
中科院分区：
文献类型：
--
作者：
Dupuy S;Lambert M;Zucman D;Choukem SP;Tognarelli S;Pages C;Lebbé C;Caillat-Zucman S
先天免疫对致癌性人类疱疹病毒 8 (HHV8) 免疫监视的贡献尚未得到深入研究。我们研究了 70 名 HHV8 感染受试者的 NK 细胞表型和功能，这些受试者要么是无症状携带者，要么患有卡波西肉瘤 (KS)。我们的结果显示健康 HHV8 携带者的 NK 细胞受体库发生了显着改变，NKp30、NKp46 和 CD161 受体的表达减少。此外，在活动性 KS 患者中观察到与 NK 细胞溶解能力受损相关的激活 NKG2D 受体的下调。治疗后 KS 的缓解伴随着 NKG2D 水平和 NK 细胞活性的恢复。 HHV8 潜伏感染的内皮细胞过表达多种 NK 细胞受体的配体，包括 NKG2D 配体。通过 KS 活检组织的免疫组织化学染色原位证实了肿瘤细胞 NKG2D 配体的强表达。然而，没有检测到肿瘤浸润的 NK 细胞，这表明 KS 微环境中 NK 细胞归巢或存活存在缺陷。在已知的 KS 衍生的免疫调节因子中，我们发现前列腺素 E2 (PGE2) 是负责静息 NK 细胞上 NKG2D 表达下调的关键元件。此外，PGE2阻止IL-15激活的NK细胞上NKG2D和NKp30受体的上调，并抑制IL-15诱导的NK细胞的增殖和存活。总而言之，我们的观察结果与独特的免疫逃避机制一致，该机制允许 HHV8 逐步逃避 NK 细胞反应，首先是在感染的早期阶段，以促进病毒潜伏期的维持，然后通过抑制 NKG2D 介导的功能来促进肿瘤细胞生长。重要的是，我们的结果为使用 PGE2 抑制剂作为治疗侵袭性 KS 的一种有吸引力的方法提供了额外的支持，因为它们可以恢复杀肿瘤 NK 细胞的活化和存活。自然杀伤 (NK) 细胞是针对病毒感染和肿瘤的先天免疫反应的一部分。它们的激活是一组识别靶细胞上特定配体的抑制性和激活性受体发出信号的最终结果。人类疱疹病毒 8 (HHV8) 是一种致癌病毒，可导致卡波西肉瘤 (KS)，这是一种多灶性血管生成肿瘤。 NK 细胞如何有助于控制 HHV8 感染和 KS 的发展尚不清楚。在本文中，我们展示了 HHV8 用于逃避 NK 细胞反应的不同策略。无症状感染或 KS 患者的 NKp30、NKp46 和 CD161 受体表达下调。此外，患有活动性 KS 的患者表现出 NKG2D 激活受体的额外下调，这与 NK 细胞对靶细胞的细胞毒性受损有关。 KS 的解决与恢复的 NKG2D 表达和细胞毒功能相关。我们提供的证据表明，NKG2D 的下调是由炎症性前列腺素 E2 (PGE2) 介导的，已知由 KS 细胞释放，并表明 PGE2 通过阻止 IL-15 介导的 NK 细胞激活发挥作用。这些结果强烈支持使用 PGE2 抑制剂作为治疗活动性 KS 的一种有吸引力的方法。
The contribution of innate immunity to immunosurveillance of the oncogenic Human Herpes Virus 8 (HHV8) has not been studied in depth. We investigated NK cell phenotype and function in 70 HHV8-infected subjects, either asymptomatic carriers or having developed Kaposi's sarcoma (KS). Our results revealed substantial alterations of the NK cell receptor repertoire in healthy HHV8 carriers, with reduced expression of NKp30, NKp46 and CD161 receptors. In addition, down-modulation of the activating NKG2D receptor, associated with impaired NK-cell lytic capacity, was observed in patients with active KS. Resolution of KS after treatment was accompanied with restoration of NKG2D levels and NK cell activity. HHV8-latently infected endothelial cells overexpressed ligands of several NK cell receptors, including NKG2D ligands. The strong expression of NKG2D ligands by tumor cells was confirmed in situ by immunohistochemical staining of KS biopsies. However, no tumor-infiltrating NK cells were detected, suggesting a defect in NK cell homing or survival in the KS microenvironment. Among the known KS-derived immunoregulatory factors, we identified prostaglandin E2 (PGE2) as a critical element responsible for the down-modulation of NKG2D expression on resting NK cells. Moreover, PGE2 prevented up-regulation of the NKG2D and NKp30 receptors on IL-15-activated NK cells, and inhibited the IL-15-induced proliferation and survival of NK cells. Altogether, our observations are consistent with distinct immunoevasion mechanisms that allow HHV8 to escape NK cell responses stepwise, first at early stages of infection to facilitate the maintenance of viral latency, and later to promote tumor cell growth through suppression of NKG2D-mediated functions. Importantly, our results provide additional support to the use of PGE2 inhibitors as an attractive approach to treat aggressive KS, as they could restore activation and survival of tumoricidal NK cells. Natural Killer (NK) cells are part of the innate immune response against virus infections and tumors. Their activation is the net result of signals emanating from a panel of inhibitory and activating receptors recognizing specific ligands on target cells. Human Herpes Virus 8 (HHV8) is an oncogenic virus responsible of Kaposi Sarcoma (KS), a multifocal angiogenic tumor. How NK cells contribute to the control of infection by HHV8 infection and development of KS, is unclear. In this paper, we show different strategies used by HHV8 to escape NK cell response. Patients with asymptomatic infection or KS have down-modulated expression of NKp30, NKp46 and CD161 receptors. In addition, patients with active KS show additional down-modulation of the NKG2D activating receptor, associated with impaired NK-cell cytotoxicity against target cells. Resolution of KS correlates with regained NKG2D expression and cytotoxic function. We present evidence that down-modulation of NKG2D is mediated by inflammatory prostaglandin E2 (PGE2), known to be released by KS cells, and show that PGE2 acts by preventing IL-15-mediated activation of NK cells. These results strongly support the use of PGE2 inhibitors as an attractive approach to treat active KS.
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