Jennings Ryan N, Grayson Jason M, Barton Erik S
Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
J Virol. 2014 Dec;88(24):14040-9. doi: 10.1128/JVI.02360-14. Epub 2014 Sep 24.
CD8(+) T cell responses are critical to the control of replication and reactivation associated with gammaherpesvirus infection. Type I interferons (IFNs) have been shown to have direct and indirect roles in supporting CD8(+) T cell development and function during viral infection; however, the role of type I interferons during latent viral infection has not been examined. Mice deficient in type I IFN signaling (IFNAR1(-/-) mice) have high levels of reactivation during infection with murine gammaherpesvirus 68 (MHV68), a murine gammaherpesvirus model for Epstein-Barr virus. We hypothesized that type I IFNs function to enhance the anti-gammaherpesvirus CD8(+) T cell response. To test this, IFNAR1(-/-) mice were infected with MHV68 and the CD8(+) T cell response was analyzed. In the absence of type I IFN signaling, there was a marked increase in short-lived effector CD8(+) T cells, and MHV68-specific CD8(+) T cells had upregulated expression of PD-1 and reduced tumor necrosis factor alpha (TNF-α), gamma IFN (IFN-γ), and interleukin-2 (IL-2) production. Suppressing MHV68 replication early in infection using the antiviral cidofovir rescued CD8(+) T cell cytokine production and reduced PD-1 expression. However, suppressing high levels of reactivation in IFNAR1(-/-) mice failed to improve CD8(+) T cell cytokine production during latency. T cell-specific abrogation of type I IFN signaling showed that the effects of type I IFNs on the CD8(+) T cell response during MHV68 infection are independent of direct type I IFN signaling on T cells. Our findings support a model in which type I IFNs likely suppress MHV68 replication, thus limiting viral antigen and facilitating an effective gammaherpesvirus-directed CD8(+) T cell response.
The murine gammaherpesvirus MHV68 has both genetic and biologic homology to the human gammaherpesvirus Epstein-Barr virus (EBV), which infects over 90% of humans. Latent EBV infection and reactivation are associated with various life-threatening diseases and malignancies. Host suppression of gammaherpesvirus latency and reactivation requires both CD8(+) T cells as well as type I interferon signaling. Type I IFNs have been shown to critically support the antiviral CD8(+) T cell response in other virus models. Here, we identify an indirect role for type I IFN signaling in enhancing gammaherpesvirus-specific CD8(+) T cell cytokine production. Further, this function of type I IFN signaling can be partially rescued by suppressing viral replication during early MHV68 infection. Our data suggest that type I IFN signaling on non-T cells can enhance CD8(+) T cell function during gammaherpesvirus infection, potentially through suppression of MHV68 replication.
CD8(+) T细胞反应对于控制与γ疱疹病毒感染相关的复制和再激活至关重要。I型干扰素（IFN）已被证明在病毒感染期间对支持CD8(+) T细胞的发育和功能具有直接和间接作用；然而，I型干扰素在潜伏性病毒感染期间的作用尚未得到研究。I型IFN信号缺陷的小鼠（IFNAR1(-/-)小鼠）在感染鼠γ疱疹病毒68（MHV68，一种用于模拟爱泼斯坦-巴尔病毒的鼠γ疱疹病毒模型）期间具有高水平的再激活。我们假设I型IFN的功能是增强抗γ疱疹病毒的CD8(+) T细胞反应。为了验证这一点，将IFNAR1(-/-)小鼠感染MHV68，并分析CD8(+) T细胞反应。在缺乏I型IFN信号的情况下，短命效应性CD8(+) T细胞显著增加，且MHV68特异性CD8(+) T细胞的程序性死亡受体1（PD-1）表达上调，肿瘤坏死因子α（TNF-α）、γ干扰素（IFN-γ）和白细胞介素-2（IL-2）的产生减少。在感染早期使用抗病毒药物西多福韦抑制MHV68复制可挽救CD8(+) T细胞细胞因子的产生并降低PD-1表达。然而，抑制IFNAR1(-/-)小鼠中的高水平再激活未能改善潜伏期间CD8(+) T细胞细胞因子的产生。T细胞特异性消除I型IFN信号表明，I型IFN在MHV68感染期间对CD8(+) T细胞反应的影响独立于T细胞上的直接I型IFN信号。我们的研究结果支持这样一种模型，即I型IFN可能抑制MHV68复制，从而限制病毒抗原并促进有效的γ疱疹病毒导向的CD8(+) T细胞反应。
鼠γ疱疹病毒MHV68与人类γ疱疹病毒爱泼斯坦-巴尔病毒（EBV）具有基因和生物学同源性，EBV感染超过90%的人类。潜伏性EBV感染和再激活与各种危及生命的疾病和恶性肿瘤相关。宿主对γ疱疹病毒潜伏和再激活的抑制需要CD8(+) T细胞以及I型干扰素信号。在其他病毒模型中，I型IFN已被证明对抗病毒CD8(+) T细胞反应至关重要。在此，我们确定了I型IFN信号在增强γ疱疹病毒特异性CD8(+) T细胞细胞因子产生中的间接作用。此外，在MHV68感染早期通过抑制病毒复制可部分挽救I型IFN信号的这一功能。我们的数据表明，非T细胞上的I型IFN信号可能通过抑制MHV68复制来增强γ疱疹病毒感染期间CD8(+) T细胞的功能。
