Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
J Virol. 2022 Jul 27;96(14):e0063922. doi: 10.1128/jvi.00639-22. Epub 2022 Jun 27.
Gammaherpesviruses, such as human Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68), are species-specific, ubiquitous pathogens that are associated with multiple cancers, including B cell lymphomas. These viruses have a natural tropism for B cells and usurp B cell differentiation to drive a unique and robust polyclonal germinal center response to establish a long-term latent reservoir in memory B cells. The robust polyclonal germinal center response driven by gammaherpesvirus infection increases the risk for B cell transformation. Unsurprisingly, many gammaherpesvirus cancers are derived from germinal center or post-germinal center B cells. The viral and host factors that influence the gammaherpesvirus-driven germinal center response are not clearly defined. We previously showed that host interleukin 17 receptor A (IL-17RA) signaling promotes the establishment of chronic MHV68 infection and the MHV68-driven germinal center response. In this study, we found that T cell-intrinsic IL-17RA signaling recapitulates some proviral aspects of global IL-17RA signaling during MHV68 infection. Specifically, we found that T cell-intrinsic IL-17RA signaling supports the MHV68-driven germinal center response, the establishment of latency in the spleen, and viral reactivation in the spleen and peritoneal cavity. Our study unveils an unexpected finding where the T cell-specific IL-17RA signaling supports the establishment of a latent reservoir of a B cell-tropic gammaherpesvirus. Gammaherpesviruses, such as human EBV, establish lifelong infection in >95% of adults and are associated with B cell lymphomas. Gammaherpesviruses usurp the germinal center response to establish latent infection, and the germinal center B cells are thought to be the target of viral transformation. We previously found that global expression of IL-17RA promotes the establishment of chronic MHV68 infection and the MHV68-driven germinal center response. In this study, we showed that T cell-intrinsic IL-17RA signaling is necessary to promote the MHV68-driven germinal center response by supporting CD4 T follicular helper cell expansion. We also found that T cell-intrinsic IL-17RA signaling contributes to but is not solely responsible for the systemic proviral role of IL-17RA signaling, highlighting the multifaceted function of IL-17RA signaling during MHV68 infection.
γ 疱疹病毒，如人类 Epstein-Barr 病毒（EBV）和鼠 γ 疱疹病毒 68（MHV68），是具有物种特异性的普遍存在的病原体，与多种癌症有关，包括 B 细胞淋巴瘤。这些病毒对 B 细胞具有天然的趋向性，并篡夺 B 细胞分化，以驱动独特而强烈的多克隆生发中心反应，从而在记忆 B 细胞中建立长期潜伏的储库。γ 疱疹病毒感染驱动的强烈多克隆生发中心反应增加了 B 细胞转化的风险。毫不奇怪，许多 γ 疱疹病毒癌症来源于生发中心或生发中心后 B 细胞。影响 γ 疱疹病毒驱动的生发中心反应的病毒和宿主因素尚不清楚。我们之前曾表明，宿主白细胞介素 17 受体 A（IL-17RA）信号促进慢性 MHV68 感染的建立和 MHV68 驱动的生发中心反应。在这项研究中，我们发现 T 细胞内在的 IL-17RA 信号在 MHV68 感染过程中再现了全局 IL-17RA 信号的一些前病毒方面。具体来说，我们发现 T 细胞内在的 IL-17RA 信号支持 MHV68 驱动的生发中心反应、在脾脏中建立潜伏期以及在脾脏和腹腔中病毒重新激活。我们的研究揭示了一个意想不到的发现，即 T 细胞特异性 IL-17RA 信号支持 B 细胞嗜性 γ 疱疹病毒潜伏储库的建立。γ 疱疹病毒，如人类 EBV，在超过 95%的成年人中建立终身感染，与 B 细胞淋巴瘤有关。γ 疱疹病毒篡夺生发中心反应以建立潜伏感染，生发中心 B 细胞被认为是病毒转化的靶标。我们之前发现，IL-17RA 的全局表达促进慢性 MHV68 感染的建立和 MHV68 驱动的生发中心反应。在这项研究中，我们表明 T 细胞内在的 IL-17RA 信号通过支持 CD4 T 滤泡辅助细胞的扩增来促进 MHV68 驱动的生发中心反应是必要的。我们还发现，T 细胞内在的 IL-17RA 信号有助于但不是唯一负责 IL-17RA 信号的全身前病毒作用，突出了 IL-17RA 信号在 MHV68 感染过程中的多方面功能。
