Neal Z C, Splitter G A
Department of Animal Health and Biomedical Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
J Virol. 1998 Oct;72(10):8052-60. doi: 10.1128/JVI.72.10.8052-8060.1998.
Although the ability of serum-neutralizing antibodies to protect against picornavirus infection is well established, the contribution of cell-mediated immunity to protection is uncertain. Using major histocompatibility complex class II-deficient (RHAbeta-/-) mice, which are unable to mediate CD4(+) T-lymphocyte-dependent humoral responses, we demonstrated antibody-independent protection against lethal encephalomyocarditis virus (EMCV) infection in the natural host. The majority of RHAbeta-/- mice inoculated with 10(4) PFU of attenuated Mengo virus (vMC24) resolved infection and were resistant to lethal challenge with the highly virulent, serotypically identical cardiovirus, EMCV. Protection in these mice was in the absence of detectable serum-neutralizing antibodies. Depletion of CD8(+) T lymphocytes prior to lethal EMCV challenge ablated protection in vMC24-immunized RHAbeta-/- mice. The CD8(+) T-lymphocyte-dependent protection observed in vivo may, in part, be the result of cytotoxic T-lymphocyte (CTL) activity, as CD8(+) T splenocytes exhibited in vitro cytolysis of EMCV-infected targets. The existence of virus-specific CD8(+) T-lymphocyte memory in these mice was demonstrated by increased expression of cell surface activation markers CD25, CD69, CD71, and CTLA-4 following antigen-specific reactivation in vitro. Although recall response in vMC24-immunized RHAbeta-/- mice was intact and effectual shortly after immunization, protection abated over time, as only 3 of 10 vMC24-immunized RHAbeta-/- mice survived when rechallenged 90 days later. The present study demonstrating CD8(+) T-lymphocyte-dependent protection in the absence of serum-neutralizing antibodies, coupled with our previous results indicating that vMC24-specific CD4(+) T lymphocytes confer protection against lethal EMCV in the absence of prophylactic antibodies, suggests the existence of nonhumoral protective mechanisms against picornavirus infections.
尽管血清中和抗体预防小核糖核酸病毒感染的能力已得到充分证实，但细胞介导的免疫对预防感染的作用尚不确定。利用主要组织相容性复合体II类缺陷（RHAbeta-/-）小鼠（其无法介导CD4(+) T淋巴细胞依赖性体液反应），我们在天然宿主中证明了针对致死性脑心肌炎病毒（EMCV）感染的抗体非依赖性保护作用。大多数接种10(4) PFU减毒Mengo病毒（vMC24）的RHAbeta-/-小鼠清除了感染，并对高毒力、血清型相同的心肌炎病毒EMCV的致死性攻击具有抗性。这些小鼠中的保护作用在没有可检测到的血清中和抗体的情况下依然存在。在致死性EMCV攻击前耗尽CD8(+) T淋巴细胞消除了vMC24免疫的RHAbeta-/-小鼠中的保护作用。在体内观察到的CD8(+) T淋巴细胞依赖性保护作用，部分可能是细胞毒性T淋巴细胞（CTL）活性的结果，因为CD8(+) T脾细胞在体外表现出对EMCV感染靶标的细胞溶解作用。这些小鼠中病毒特异性CD8(+) T淋巴细胞记忆的存在通过体外抗原特异性再激活后细胞表面活化标志物CD25、CD69、CD71和CTLA-4表达的增加得以证明。尽管vMC24免疫的RHAbeta-/-小鼠在免疫后不久的回忆反应完整且有效，但保护作用随时间减弱，因为在90天后再次攻击时，10只vMC24免疫的RHAbeta-/-小鼠中只有3只存活。本研究证明在没有血清中和抗体的情况下存在CD8(+) T淋巴细胞依赖性保护作用，再加上我们之前的结果表明vMC24特异性CD4(+) T淋巴细胞在没有预防性抗体的情况下赋予针对致死性EMCV的保护作用，提示存在针对小核糖核酸病毒感染的非体液保护机制。
