Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence
Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence
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DOI：
10.1371/journal.ppat.1006050
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发表时间：
2016-12-01
期刊：
影响因子：
6.7
通讯作者：
Humphreys, Ian R.
中科院分区：
文献类型：
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作者：
Clement, Mathew;Marsden, Morgan;Humphreys, Ian R.
CD 4（+）T细胞支持宿主防御疱疹病毒和其他病毒病原体。我们发现，感染β-疱疹病毒科人巨细胞病毒（HCMV）或鼠巨细胞病毒（MCMV）的宿主的全身和粘膜组织中的CD 4（+）T细胞表达调节性细胞因子白细胞介素（IL）-10。IL-10（+）CD 4（+）T细胞共表达TH 1相关转录因子和趋化因子受体。缺乏T细胞来源的IL-10的小鼠引起增强的抗病毒T细胞应答，并限制MCMV在唾液腺中的持久性和唾液中的分泌。因此，IL-10（+）CD 4（+）T细胞抑制针对CMV的抗病毒免疫应答。IL-27促进外周中该T细胞群的扩增，而粘膜IL-10（+）T细胞应答是ICOS依赖性的。外周IL-10（+）CD 4（+）T细胞蓄积减少的感染的IL-27 ra缺陷小鼠显示出稳健的T细胞应答和限制的MCMV持续和脱落。时间抑制实验表明，IL-27 R信号在初始感染的抑制T细胞免疫和控制病毒脱落在MCMV的持久性。IL-27的产生是由I型IFN促进的，这表明β-疱疹病毒科利用这种抗病毒途径的免疫调节特性来建立慢性。此外，我们的数据表明，在初始感染细胞因子信号事件深刻影响病毒慢性化。
CD4(+) T cells support host defence against herpesviruses and other viral pathogens. We identified that CD4(+) T cells from systemic and mucosal tissues of hosts infected with the beta-herpesviridae human cytomegalovirus (HCMV) or murine cytomegalovirus (MCMV) express the regulatory cytokine interleukin (IL)-10. IL-10(+)CD4(+) T cells co-expressed TH1-associated transcription factors and chemokine receptors. Mice lacking T cell-derived IL-10 elicited enhanced antiviral T cell responses and restricted MCMV persistence in salivary glands and secretion in saliva. Thus, IL-10(+) CD4(+) T cells suppress antiviral immune responses against CMV. Expansion of this T-cell population in the periphery was promoted by IL-27 whereas mucosal IL-10(+) T cell responses were ICOS-dependent. Infected Il27ra-deficient mice with reduced peripheral IL-10(+)CD4(+) T cell accumulation displayed robust T cell responses and restricted MCMV persistence and shedding. Temporal inhibition experiments revealed that IL-27R signaling during initial infection was required for the suppression of T cell immunity and control of virus shedding during MCMV persistence. IL-27 production was promoted by type-I IFN, suggesting that beta-herpesviridae exploit the immune-regulatory properties of this antiviral pathway to establish chronicity. Further, our data reveal that cytokine signaling events during initial infection profoundly influence virus chronicity.