Wu Zeguang, Frascaroli Giada, Bayer Carina, Schmal Tatjana, Mertens Thomas
Institute of Virology, Ulm University Medical Center, Ulm, Germany.
Institute of Virology, Ulm University Medical Center, Ulm, Germany
J Virol. 2015 Jun;89(12):6435-41. doi: 10.1128/JVI.00435-15. Epub 2015 Apr 8.
Control of human cytomegalovirus (HCMV) requires a continuous immune surveillance, thus HCMV is the most important viral pathogen in severely immunocompromised individuals. Both innate and adaptive immunity contribute to the control of HCMV. Here, we report that peripheral blood natural killer cells (PBNKs) from HCMV-seropositive donors showed an enhanced activity toward HCMV-infected autologous macrophages. However, this enhanced response was abolished when purified NK cells were applied as effectors. We demonstrate that this enhanced PBNK activity was dependent on the interleukin-2 (IL-2) secretion of CD4(+) T cells when reexposed to the virus. Purified T cells enhanced the activity of purified NK cells in response to HCMV-infected macrophages. This effect could be suppressed by IL-2 blocking. Our findings not only extend the knowledge on the immune surveillance in HCMV-namely, that NK cell-mediated innate immunity can be enhanced by a preexisting T cell antiviral immunity-but also indicate a potential clinical implication for patients at risk for severe HCMV manifestations due to immunosuppressive drugs, which mainly suppress IL-2 production and T cell responsiveness.
Human cytomegalovirus (HCMV) is never cleared by the host after primary infection but instead establishes a lifelong latent infection with possible reactivations when the host's immunity becomes suppressed. Both innate immunity and adaptive immunity are important for the control of viral infections. Natural killer (NK) cells are main innate effectors providing a rapid response to virus-infected cells. Virus-specific T cells are the main adaptive effectors that are critical for the control of the latent infection and limitation of reinfection. In this study, we found that IL-2 secreted by adaptive CD4(+) T cells after reexposure to HCMV enhances the activity of NK cells in response to HCMV-infected target cells. This is the first direct evidence that the adaptive T cells can help NK cells to act against HCMV infection.
对人巨细胞病毒（HCMV）的控制需要持续的免疫监视，因此HCMV是严重免疫受损个体中最重要的病毒病原体。固有免疫和适应性免疫都有助于控制HCMV。在此，我们报告来自HCMV血清阳性供体的外周血自然杀伤细胞（PBNK）对HCMV感染的自体巨噬细胞表现出增强的活性。然而，当使用纯化的NK细胞作为效应细胞时，这种增强的反应被消除。我们证明，当再次暴露于病毒时，这种增强的PBNK活性依赖于CD4(+) T细胞分泌的白细胞介素-2（IL-2）。纯化的T细胞增强了纯化的NK细胞对HCMV感染巨噬细胞的反应活性。这种效应可被IL-2阻断所抑制。我们的发现不仅扩展了关于HCMV免疫监视的知识，即预先存在的T细胞抗病毒免疫可增强NK细胞介导的固有免疫，而且还表明对于因免疫抑制药物而有严重HCMV表现风险的患者具有潜在的临床意义，免疫抑制药物主要抑制IL-2产生和T细胞反应性。
人巨细胞病毒（HCMV）在初次感染后从未被宿主清除，而是建立终身潜伏感染，当宿主免疫力受到抑制时可能重新激活。固有免疫和适应性免疫对于控制病毒感染都很重要。自然杀伤（NK）细胞是主要的固有效应细胞，对病毒感染细胞提供快速反应。病毒特异性T细胞是主要的适应性效应细胞，对控制潜伏感染和限制再感染至关重要。在本研究中，我们发现再次暴露于HCMV后适应性CD4(+) T细胞分泌的IL-2增强了NK细胞对HCMV感染靶细胞的反应活性。这是适应性T细胞可帮助NK细胞对抗HCMV感染的首个直接证据。
