Role of PKR and Type I IFNs in viral control during primary and secondary infection.
Role of PKR and Type I IFNs in viral control during primary and secondary infection.
复制标题
DOI：
10.1371/journal.ppat.1000966
复制
发表时间：
2010-06-24
期刊：
影响因子：
6.7
通讯作者：
Suresh M
中科院分区：
文献类型：
--
作者：
Nakayama Y;Plisch EH;Sullivan J;Thomas C;Czuprynski CJ;Williams BR;Suresh M
已知I型干扰素(IFN)可介导病毒控制，也可促进病毒特异性CD8+T细胞的存活和扩增。然而，目前尚不清楚引发这些不同细胞效应的信号级联是否也是不同的。I型IFN的抗病毒信号机制之一是由干扰素诱导的dsRNA激活的蛋白激酶PKR介导的。在这里，我们研究了PKR和I型IFN在调节病毒清除和CD8+T细胞在原发和继发病毒感染中的作用。我们的研究表明，在小鼠初次感染淋巴细胞性脉络膜脑膜炎病毒(LCMV)期间，在病毒控制和激发CD8+T细胞反应过程中对PKR的不同需求。PKR基因缺陷的小鼠产生了强大的CD8+T细胞反应，但未能有效地控制LCMV。在没有PKR的情况下，LCMV的控制是多因素的，与CD8+T细胞介导的病毒抑制作用降低、细胞内病毒复制增强以及干扰素反应基因的稳定表达水平降低有关。此外，我们发现，尽管记忆CD8+T细胞在二次反应中正常扩张并分化为效应者，但有效清除LCMV而不是痘苗病毒需要感染细胞中的PKR活性。在缺乏I型干扰素信号的情况下，次级效应CD8+T细胞在体内对LCMV和痘苗病毒的复制都没有作用。这些发现提供了对I型干扰素作用的细胞途径的洞察，并强调了在继发感染期间病毒控制的先天免疫机制的重要性被低估，尽管记忆CD8+T细胞的反应加速。此外，本文的结果进一步加深了我们对抗病毒保护性免疫的免疫相关性的理解，这对疫苗的合理设计具有重要意义。I型干扰素是抵御病毒感染的第一道防线，促进树突状细胞的抗原提呈，在直接刺激抗病毒T细胞应答中发挥重要作用。然而，I型干扰素的不同细胞效应的潜在机制还没有很好的定义。I型干扰素诱导的抗病毒信号转导机制之一是由干扰素诱导的dsRNA激活的蛋白激酶PKR介导的。我们发现，在急性淋巴细胞性脉络膜脑膜炎病毒(LCMV)感染期间，对细胞PKR活性的要求可能是I型干扰素作用的一个区别特征，I型干扰素作用于介导病毒控制或刺激CD8+T细胞扩张。通常，包括I型IFN在内的先天免疫机制被认为对初次感染期间的病毒控制很重要。然而，我们发现，疫苗诱导的CD8+T细胞记忆和加速产生次级效应器是必要的，但不足以在没有先天效应器PKR和I型IFN的帮助下提供对再次感染的有效保护性免疫。这些发现提高了我们对病毒-免疫系统相互作用和抗病毒保护性免疫的免疫相关性的理解，这可能对开发有效的抗病毒疫苗和免疫疗法具有指导意义。
Type I interferons (IFNs) are known to mediate viral control, and also promote survival and expansion of virus-specific CD8+ T cells. However, it is unclear whether signaling cascades involved in eliciting these diverse cellular effects are also distinct. One of the best-characterized anti-viral signaling mechanisms of Type I IFNs is mediated by the IFN-inducible dsRNA activated protein kinase, PKR. Here, we have investigated the role of PKR and Type I IFNs in regulating viral clearance and CD8+ T cell response during primary and secondary viral infections. Our studies demonstrate differential requirement for PKR, in viral control versus elicitation of CD8+ T cell responses during primary infection of mice with lymphocytic choriomeningitis virus (LCMV). PKR-deficient mice mounted potent CD8+ T cell responses, but failed to effectively control LCMV. The compromised LCMV control in the absence of PKR was multifactorial, and linked to less effective CD8+ T cell-mediated viral suppression, enhanced viral replication in cells, and lower steady state expression levels of IFN-responsive genes. Moreover, we show that despite normal expansion of memory CD8+ T cells and differentiation into effectors during a secondary response, effective clearance of LCMV but not vaccinia virus required PKR activity in infected cells. In the absence of Type I IFN signaling, secondary effector CD8+ T cells were ineffective in controlling both LCMV and vaccinia virus replication in vivo. These findings provide insight into cellular pathways of Type I IFN actions, and highlight the under-appreciated importance of innate immune mechanisms of viral control during secondary infections, despite the accelerated responses of memory CD8+ T cells. Additionally, the results presented here have furthered our understanding of the immune correlates of anti-viral protective immunity, which have implications in the rational design of vaccines. Type I interferons (IFNs) constitute the first line of defense against viral infections, promote antigen presentation by dendritic cells, and play a crucial role in directly stimulating anti-viral T cell responses. However, the mechanisms underlying the diverse cellular effects of Type I IFNs are not well defined. One of the best-characterized anti-viral signaling mechanisms induced by Type I IFNs is mediated by the IFN-inducible dsRNA activated protein kinase, PKR. We show that requirement for cellular PKR activity could be a distinguishing feature between Type I IFN actions that mediate viral control or stimulate CD8+ T cell expansion during an acute infection with lymphocytic choriomeningitis virus (LCMV). Typically, innate immune mechanisms including Type I IFNs are considered important for viral control during a primary infection. However, we find that presence of vaccine-induced CD8+ T cell memory and accelerated generation of secondary effectors are necessary but not sufficient to provide effective protective immunity to re-infection, without the aid of innate effectors PKR and Type I IFNs. These findings have improved our understanding of virus-immune system interactions and immune correlates of anti-viral protective immunity, which might have implications in the development of effective anti-viral vaccines and immunotherapies.
登录
查看更多内容
DOI：
10.1084/jem.20050821
发表时间：
2005-09-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kolumam GA;Thomas S;Thompson LJ;Sprent J;Murali-Krishna K
通讯作者：
Murali-Krishna K
影响因子：
8
作者：
Cuddihy, AR;Wong, AHT;Koromilas, AE
通讯作者：
Koromilas, AE
影响因子：
4.4
作者：
Havenar-Daughton, Colin;Kolumam, Ganesh A.;Murali-Krishna, Kaja
通讯作者：
Murali-Krishna, Kaja
影响因子：
11.4
作者：
Goh, KC;deVeer, MJ;Williams, BRG
通讯作者：
Williams, BRG
影响因子：
4.4
作者：
Durbin, JE;Fernandez-Sesma, A;Levy, DE
通讯作者：
Levy, DE