Lupfer Christopher R, Stokes Kate L, Kuriakose Teneema, Kanneganti Thirumala-Devi
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
J Virol. 2017 Aug 10;91(17). doi: 10.1128/JVI.00377-17. Print 2017 Sep 1.
Pathogen recognition receptors are vital components of the immune system. Engagement of these receptors is important not only for instigation of innate immune responses to invading pathogens but also for initiating the adaptive immune response. Members of the NOD-like receptor (NLR) family of pathogen recognition receptors have important roles in orchestrating this response. The NLR family member NLRC5 regulates major histocompatibility complex class I (MHC-I) expression during various types of infections, but its role in immunity to influenza A virus (IAV) is not well studied. Here we show that mice exhibit an altered CD8 T cell response during IAV infection compared to that of wild-type (WT) mice. mice have decreased MHC-I expression on hematopoietic cells and fewer CD8 T cells prior to infection. NLRC5 deficiency does not affect the generation of antigen-specific CD8 T cells following IAV infection; however, a change in epitope dominance is observed in mice. Moreover, IAV-specific CD8 T cells from mice have impaired effector functions. This change in the adaptive immune response is associated with impaired viral clearance in mice. Collectively, our results demonstrate an important role for NLRC5 in regulation of antiviral immune responses and viral clearance during IAV infection. The NOD-like receptor family member NLRC5 is known to regulate expression of MHC-I as well as other genes required for antigen processing. In addition, NLRC5 also regulates various immune signaling pathways. In this study, we investigated the role of NLRC5 during influenza virus infection and found a major role for NLRC5 in restricting virus replication and promoting viral clearance. The observed increases in viral titers in NLRC5-deficient mice correlated with impaired effector CD8 T cell responses. Although NLRC5-deficient mice were defective at clearing the virus, they did not show an increase in morbidity or mortality following influenza virus infection because of other compensatory immune mechanisms. Therefore, our study highlights how NLRC5 regulates multiple immune effector mechanisms to promote the host defense during influenza virus infection.
病原体识别受体是免疫系统的重要组成部分。这些受体的激活不仅对于引发针对入侵病原体的固有免疫反应很重要，而且对于启动适应性免疫反应也很重要。病原体识别受体的NOD样受体（NLR）家族成员在协调这种反应中发挥着重要作用。NLR家族成员NLRC5在各种类型的感染过程中调节主要组织相容性复合体I类（MHC-I）的表达，但其在甲型流感病毒（IAV）免疫中的作用尚未得到充分研究。在这里，我们表明，与野生型（WT）小鼠相比，NLRC5缺陷小鼠在IAV感染期间表现出改变的CD8 T细胞反应。NLRC5缺陷小鼠在感染前造血细胞上的MHC-I表达降低，CD8 T细胞数量减少。NLRC5缺陷不影响IAV感染后抗原特异性CD8 T细胞的产生；然而，在NLRC5缺陷小鼠中观察到表位优势的变化。此外，来自NLRC5缺陷小鼠的IAV特异性CD8 T细胞的效应功能受损。适应性免疫反应的这种变化与NLRC5缺陷小鼠中病毒清除受损有关。总的来说，我们的结果证明了NLRC5在IAV感染期间调节抗病毒免疫反应和病毒清除中的重要作用。已知NOD样受体家族成员NLRC5调节MHC-I以及抗原加工所需的其他基因的表达。此外，NLRC5还调节各种免疫信号通路。在这项研究中，我们研究了NLRC5在流感病毒感染期间的作用，发现NLRC5在限制病毒复制和促进病毒清除中起主要作用。在NLRC5缺陷小鼠中观察到的病毒滴度增加与效应CD8 T细胞反应受损相关。尽管NLRC5缺陷小鼠在清除病毒方面存在缺陷，但由于其他补偿性免疫机制，它们在流感病毒感染后并未表现出发病率或死亡率的增加。因此，我们的研究突出了NLRC5如何调节多种免疫效应机制以促进流感病毒感染期间的宿主防御。
