Human Cytomegalovirus (HCMV)-Specific CD4+ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro
Human Cytomegalovirus (HCMV)-Specific CD4+ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro
复制标题
DOI：
10.1128/jvi.02128-16
复制
发表时间：
2017-03-01
影响因子：
5.4
通讯作者：
Wills, Mark R.
中科院分区：
文献类型：
--
作者：
Jackson, Sarah E.;Sedikides, George X.;Wills, Mark R.
人巨细胞病毒（HCMV）感染和周期性再激活通常在健康人群中由HCMV特异性T细胞反应控制。虽然CD 8（+）T细胞对HCMV的反应已被广泛研究，但HCMV特异性CD 4（+）T细胞效应器反应并不清楚，特别是在与HCMV感染细胞直接相互作用的情况下。我们筛选了γ干扰素（IFN-γ）和白细胞介素-10（IL-10）的反应，6 HCMV肽池（pp 65，pp 71，IE 1，IE 2，gB，和US 3，选择，因为他们是最频繁的肽在我们以前的研究）在84个23至74岁的捐助者。HCMV特异性CD 4（+）T细胞对pp 65、IE 1、IE 2和gB的应答主要偏向于Th 1，随着年龄的增长，这些应答既不丧失也不积累。较大比例的供体产生对pp 71和US 3的IL-10应答，但IFN-（γ）应答仍然占主导地位。研究的HCMV蛋白特异性CD 4（+）T细胞主要是效应记忆细胞，并产生细胞毒性（CD 107 a表达）和细胞因子（巨噬细胞炎症蛋白1 β分泌）效应应答。重要的是，当我们在体外测量CD 4（+）T细胞对巨细胞病毒（CMV）感染的树突状细胞的反应时，我们观察到CD 4（+）T细胞产生一系列细胞毒性和分泌效应子功能，尽管存在CMV编码的免疫逃避分子。在体外试验中，CD 4（+）T细胞对HCMV感染的树突状细胞的反应足以控制病毒的传播。总之，结果表明，HCMV特异性的CD 4（+）T细胞反应，即使是来自老年人的，也是高度功能性的，直接抗病毒。重要性人巨细胞病毒（HCMV）感染是终身携带的，在健康人群中，免疫系统可以控制HCMV感染。HCMV已经进化出许多机制来逃避免疫反应，这可能解释了为什么病毒在宿主的一生中从未被消除。与HCMV长期携带相关的免疫细胞功能障碍与老年人对新病原体和疫苗的反应不良有关。在这项研究中，我们研究了所有年龄段的健康供体中免疫细胞（CD 4（+）T细胞）对HCMV蛋白的反应，我们证明了CD 4（+）T细胞的功能得以维持。我们还表明，CD 4（+）T细胞产生效应功能，以响应HCMV感染的细胞，并可以防止病毒传播。我们的工作表明，这些HCMV特异性免疫细胞保留了许多重要的功能，并有助于预防健康老年人的有害HCMV疾病。
Human cytomegalovirus (HCMV) infection and periodic reactivation are generally well controlled by the HCMV-specific T cell response in healthy people. While the CD8(+) T cell response to HCMV has been extensively studied, the HCMV-specific CD4(+) T cell effector response is not as well understood, especially in the context of direct interactions with HCMV-infected cells. We screened the gamma interferon (IFN-gamma) and interleukin-10 (IL-10) responses to 6 HCMV peptide pools (pp65, pp71, IE1, IE2, gB, and US3, selected because they were the peptides most frequently responded to in our previous studies) in 84 donors aged 23 to 74 years. The HCMV-specific CD4(+) T cell response to pp65, IE1, IE2, and gB was predominantly Th1 biased, with neither the loss nor the accumulation of these responses occurring with increasing age. A larger proportion of donors produced an IL-10 response to pp71 and US3, but the IFN-(gamma) response was still dominant. CD4(+) T cells specific to the HCMV proteins studied were predominantly effector memory cells and produced both cytotoxic (CD107a expression) and cytokine (macrophage inflammatory protein 1 beta secretion) effector responses. Importantly, when we measured the CD4(+) T cell response to cytomegalovirus (CMV)-infected dendritic cells in vitro, we observed that the CD4(+) T cells produced a range of cytotoxic and secretory effector functions, despite the presence of CMV-encoded immune evasion molecules. CD4(+) T cell responses to HCMV-infected dendritic cells were sufficient to control the dissemination of virus in an in vitro assay. Together, the results show that HCMV-specific CD4(+) T cell responses, even those from elderly individuals, are highly functional and are directly antiviral.IMPORTANCE Human cytomegalovirus (HCMV) infection is carried for a lifetime and in healthy people is kept under control by the immune system. HCMV has evolved many mechanisms to evade the immune response, possibly explaining why the virus is never eliminated during the host's lifetime. The dysfunction of immune cells associated with the long-term carriage of HCMV has been linked with poor responses to new pathogens and vaccines when people are older. In this study, we investigated the response of a subset of immune cells (CD4(+) T cells) to HCMV proteins in healthy donors of all ages, and we demonstrate that the functionality of CD4(+) T cells is maintained. We also show that CD4(+) T cells produce effector functions in response to HCMV-infected cells and can prevent virus spread. Our work demonstrates that these HCMV-specific immune cells retain many important functions and help to prevent deleterious HCMV disease in healthy older people.