Plasmacytoid dendritic cells are dispensable or detrimental in murine systemic or respiratory viral infections.

IF 27.6 1区 医学 Q1 IMMUNOLOGY
Clemence Ngo, Camille Pierini-Malosse, Khalissa Rahmani, Michael Valente, Nils Collinet, Gilles Bessou, Capucine Guerry, Manon Fabregue, Solene Mathieu, Sarah Sharkaoui, Sophie Mazzoli, Amandine Sansoni, Frederic Fiore, Caroline Laprie, Lena Alexopoulou, Mauro Gaya, Claude Gregoire, Achille Broggi, Sarah Wurbel, Réjane Rua, Narjess Haidar, Pierre Milpied, Bertrand Escalière, Thien Phong Vu Manh, Mathieu Fallet, Lionel Chasson, Hien Tran, Thomas Baranek, Marc Le Bert, Bernard Malissen, Ana Zarubica, Marc Dalod, Elena Tomasello
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Abstract

Plasmacytoid dendritic cells (pDCs) are major producers of type I/III interferons. As interferons are crucial for antiviral defense, pDCs are assumed to play an essential role in this process; however, robust evidence supporting this dogma is scarce. Genetic or pharmacological manipulations that eliminate pDCs or disrupt their interferon production often affect other cells, confounding interpretation. Here, to overcome this issue, we engineered pDC-less mice that are specifically and constitutively devoid of pDCs by expressing diphtheria toxin under coordinated control of the Siglech and Pacsin1 genes, uniquely coexpressed in pDCs. pDC-less mice mounted protective immunity against systemic infection with mouse cytomegalovirus and showed higher survival and less lung immunopathology to intranasal infection with influenza virus and SARS-CoV-2. Thus, contrary to the prevailing dogma, we revealed that pDCs and their interferons are dispensable or deleterious during several viral infections. pDC-less mice will enable rigorously reassessing the roles of pDCs in health and disease.

浆细胞样树突状细胞在小鼠全身或呼吸道病毒感染中是可有可无或有害的。
浆细胞样树突状细胞(pDCs)是I/III型干扰素的主要生产者。由于干扰素对抗病毒防御至关重要,人们认为pDCs在这一过程中起着至关重要的作用;然而,支持这一论断的有力证据很少。消除pDCs或破坏其干扰素产生的遗传或药理学操作通常会影响其他细胞,使解释混淆。在这里,为了克服这个问题,我们通过在pDCs中唯一共表达的Siglech和Pacsin1基因的协调控制下表达白喉毒素,设计了不含pDCs的小鼠,使其特异性和组成性地缺乏pDCs。无dc小鼠对小鼠巨细胞病毒全身感染具有保护性免疫,对流感病毒和SARS-CoV-2鼻内感染表现出更高的存活率和更少的肺部免疫病理。因此,与流行的教条相反,我们揭示了pdc及其干扰素在几种病毒感染中是可有可无或有害的。不含pDCs的小鼠将能够严格地重新评估pDCs在健康和疾病中的作用。
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来源期刊
Nature Immunology
Nature Immunology 医学-免疫学
CiteScore
40.00
自引率
2.30%
发文量
248
审稿时长
4-8 weeks
期刊介绍: Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.
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