Laboratory of Innate Immunity, National Institute of Immunology, New Delhi, India.
Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, India.
Front Immunol. 2021 Nov 17;12:758190. doi: 10.3389/fimmu.2021.758190. eCollection 2021.
Plasmacytoid dendritic cells (pDCs) are the key producers of type I interferons (IFNs), thus playing a central role in initiating antiviral immune response. Besides robust type I IFN production, pDCs also act as antigen presenting cells post immunogenic stimulation. Transcription factor is indispensable for the development of both pDC and cDC1 subset. However, the mechanism underlying the differential regulation by IRF8 in cDC1- and pDC-specific genomic architecture of developmental pathways still remains to be fully elucidated. Previous studies indicated that the mutation specifically abrogates development of cDC1 without affecting that of pDC. In the present study using RNA-seq based approach, we have found that though the point mutation did not affect pDC development, it led to defective type I IFN production, thus resulting in inefficient antiviral response. This observation unraveled the distinctive roles of IRF8 in these two subpopulations-regulating the development of cDC1 whereas modulating the functionality of pDCs without affecting development. We have reported here that mutation also caused defect in production of ISGs as well as defective upregulation of costimulatory molecules in pDCs in response to NDV infection (or CpG stimulation). Through studies, we demonstrated that abrogation of type I IFN production was concomitant with reduced upregulation of costimulatory molecules in pDCs and increased NDV burden in IRF8 mice in comparison with wild type, indicating inefficient viral clearance. Further, we have also shown that mutation abolished the activation of type I IFN promoter by IRF8, justifying the low level of type I IFN production. Taken together, our study signifies that the single point mutation in , severely compromised type I IFN-mediated immune response by murine pDCs, thereby causing impairment in antiviral immunity.
浆细胞样树突状细胞（pDCs）是 I 型干扰素（IFNs）的主要产生者，因此在启动抗病毒免疫反应中发挥核心作用。除了强大的 I 型 IFN 产生外，pDCs 在免疫原性刺激后还作为抗原呈递细胞发挥作用。转录因子 对于 pDC 和 cDC1 亚群的发育都是必不可少的。然而，IRF8 在 cDC1 和 pDC 特异性发育途径的基因组结构中的差异调控的机制仍有待充分阐明。先前的研究表明， 突变特异性地阻断了 cDC1 的发育，而不影响 pDC 的发育。在本研究中，我们使用基于 RNA-seq 的方法发现，尽管点突变 没有影响 pDC 的发育，但它导致 I 型 IFN 产生缺陷，从而导致抗病毒反应效率低下。这一观察结果揭示了 IRF8 在这两个亚群中的独特作用——调节 cDC1 的发育，同时调节 pDC 而不影响其发育的功能。我们在这里报道， 突变还导致 pDC 中 ISGs 的产生缺陷以及对 NDV 感染（或 CpG 刺激）的共刺激分子的上调缺陷。通过 研究，我们证明了在与野生型相比，IRF8 小鼠中 IFN 产生的阻断伴随着 pDC 中共刺激分子的上调减少和 NDV 负担增加，表明病毒清除效率低下。此外，我们还表明， 突变消除了 IRF8 对 I 型 IFN 启动子的激活，这解释了 IFN 产生水平低的原因。总之，我们的研究表明， 中的单点突变严重损害了小鼠 pDC 中的 I 型 IFN 介导的免疫反应，从而导致抗病毒免疫受损。
