T Cell-Intrinsic Interferon Regulatory Factor 1 Expression Suppresses Differentiation of CD4+ T Cell Populations That Support Chronic Gammaherpesvirus Infection.
T Cell-Intrinsic Interferon Regulatory Factor 1 Expression Suppresses Differentiation of CD4+ T Cell Populations That Support Chronic Gammaherpesvirus Infection.
复制标题
T 细胞内在干扰素调节因子 1 表达抑制支持慢性伽玛疱疹病毒感染的 CD4 T 细胞群的分化。
DOI：
10.1128/jvi.00726-21
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发表时间：
2021
影响因子：
5.4
通讯作者：
Tarakanova,VL
中科院分区：
文献类型：
--
作者：
Jondle,CN;Johnson,KE;Mboko,WP;Tarakanova,VL
γ疱疹病毒是普遍存在的病原体，其建立终身感染并与B细胞淋巴瘤相关。为了建立慢性感染，这些病毒会篡夺B细胞分化并驱动强大的生发中心反应，以扩大潜伏的病毒库并进入记忆B细胞。生殖中心B细胞虽然对潜伏感染的建立很重要，但也被认为是病毒转化的靶点。影响γ疱疹病毒驱动的生发中心反应的宿主和病毒因素尚未明确定义。我们表明，全球表达的抗病毒和肿瘤抑制干扰素调节因子1（IRF-1）选择性地减弱小鼠γ疱疹病毒68（MHV 68）驱动的生发中心反应，并限制了潜伏病毒库的扩张。在这项研究中，我们发现，T细胞内在的IRF-1的表达概括了IRF-1在慢性MHV 68感染期间施加的抗病毒状态的某些方面，包括生发中心反应的衰减和脾脏中的病毒潜伏期。我们还发现，整体和T细胞内在IRF-1缺陷导致白细胞介素-17A（IL-17 A）表达和滤泡辅助T细胞群（支持慢性MHV 68感染的两种CD 4 +T细胞亚群）不受阻碍地增加。因此，本研究揭示了IRF-1的抗病毒活性的一个新方面，通过证明IRF-1介导的特异性CD 4 +T细胞亚群的抑制，支持慢性γ疱疹病毒infection.IMPORTANCEGammaherpesviruses感染超过95%的成年人群，最后的主机的寿命，并与多种癌症。这些病毒篡夺生殖中心的反应，在记忆B细胞中建立终身感染。这种病毒对B细胞分化的操纵被认为有助于淋巴瘤的发生，尽管病毒在体内究竟是如何促成恶性转化的还不清楚。IRF-1是一种宿主转录因子和已知的肿瘤抑制因子，以B细胞外源性方式限制MHV 68驱动的生发中心反应。我们发现T细胞内在IRF-1表达通过限制CD 4+滤泡辅助性T细胞群来减弱MHV 68驱动的生发中心反应。此外，我们的研究将IRF-1鉴定为IL-17驱动的免疫应答的新型负调节剂，突出了IRF-1在γ疱疹病毒感染中的多方面作用。
Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection and are associated with B cell lymphomas. To establish chronic infection, these viruses usurp B cell differentiation and drive a robust germinal center response to expand the latent viral reservoir and gain access to memory B cells. Germinal center B cells, while important for the establishment of latent infection, are also thought to be the target of viral transformation. The host and viral factors that impact the gammaherpesvirus-driven germinal center response are not clearly defined. We show that the global expression of the antiviral and tumor suppressor interferon regulatory factor 1 (IRF-1) selectively attenuates the murine gammaherpesvirus 68 (MHV68)-driven germinal center response and restricts the expansion of the latent viral reservoir. In this study, we found that T cell-intrinsic IRF-1 expression recapitulates some aspects of the antiviral state imposed by IRF-1 during chronic MHV68 infection, including the attenuation of the germinal center response and viral latency in the spleen. We also discovered that global and T cell-intrinsic IRF-1 deficiency leads to an unhindered rise of interleukin-17A (IL-17A)-expressing and follicular helper T cell populations, two CD4+T cell subsets that support chronic MHV68 infection. Thus, this study unveils a novel aspect of the antiviral activity of IRF-1 by demonstrating IRF-1-mediated suppression of specific CD4+T cell subsets that support chronic gammaherpesvirus infection.IMPORTANCEGammaherpesviruses infect over 95% of the adult population, last the lifetime of the host, and are associated with multiple cancers. These viruses usurp the germinal center response to establish lifelong infection in memory B cells. This manipulation of B cell differentiation by the virus is thought to contribute to lymphomagenesis, although exactly how the virus precipitates malignant transformationin vivois unclear. IRF-1, a host transcription factor and a known tumor suppressor, restricts the MHV68-driven germinal center response in a B cell-extrinsic manner. We found that T cell-intrinsic IRF-1 expression attenuates the MHV68-driven germinal center response by restricting the CD4+T follicular helper population. Furthermore, our study identified IRF-1 as a novel negative regulator of IL-17-driven immune responses, highlighting the multifaceted role of IRF-1 in gammaherpesvirus infection.