Chronic LCMV infection regulates the effector T cell response by inducing the generation of less immunogenic dendritic cells.
Chronic LCMV infection regulates the effector T cell response by inducing the generation of less immunogenic dendritic cells.
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DOI：
10.1038/s12276-023-00991-5
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发表时间：
2023-05
影响因子：
12.8
通讯作者：
Ha, Sang-Jun
中科院分区：
文献类型：
--
作者：
Yoo, Seungbo;Jeong, Yun Hee;Choi, Hong-Hee;Chae, Sehyun;Hwang, Daehee;Shin, Sung Jae;Ha, Sang-Jun
慢性病毒感染会损害宿主的全身免疫力；然而，慢性病毒感染中免疫细胞功能障碍的机制尚不完全清楚。在这项研究中，我们使用慢性淋巴细胞脉络膜脑膜炎病毒（LCMV）感染模型研究了慢性病毒感染期间造血干细胞（HSC）的谱系分化，以阐明树突状细胞（DC）分化的变化以及随后对T细胞功能的影响。我们首先研究了骨髓（BM）中造血干细胞（HSC）的谱系分化，以阐明免疫细胞分化的调节，发现其分化受到高度限制的群体是共同骨髓祖细胞（CMP）和共同树突细胞祖细胞（CDP）。有趣的是，BM 中感染 LCMV Clone 13 (CL13) 的主要免疫细胞是 CD11b/c+ 骨髓 DC。接下来我们表征了在慢性 LCMV 感染期间分化的 CD11b+ DC。这些 DC 表现出比幼稚或急性感染小鼠的 DC 更低的免疫原性表型，显示 CD80 低表达，但 PD-L1、B7-H4、IDO、TGF-β 和 IL-10 高表达。因此，这些 CD11b+ DC 诱导出效率较低的 CD8+ T 细胞和更多的 Foxp3+ 调节性 T (Treg) 细胞。此外，CL13感染期间产生的CD11b+ DC不能诱导针对新入侵病原体抗原的有效CD8+ T细胞。我们的研究结果表明，慢性病毒感染期间从 BM 产生的 DC 不能激活针对新进入抗原以及持久抗原本身的全功能效应 CD8+ T 细胞，这表明慢性病毒感染期间 T 细胞免疫反应功能改变的潜在原因。持续的病毒感染会损害免疫系统树突状细胞协调适当的抗病原体防御的能力，这一发现可能会带来慢性病毒性疾病的新疗法。韩国首尔延世大学的 Seungbo Yoo、Yun Hee Jeong 和 Sang-Jun Ha 及其同事研究了感染淋巴细胞脉络膜脑膜炎病毒 (LCMV) 的小鼠，这种病毒由啮齿动物携带，可导致人类神经系统疾病。他们表明，该病毒位于动物的骨髓内，它改变了树突状细胞的形成方式。这些免疫前哨细胞通常会将病毒入侵者的碎片呈现给抗病毒 T 细胞，以便它们发起攻击。在感染 LCMV 的小鼠中，树突状细胞表达较少的免疫刺激分子和较多的抑制分子，导致免疫反应较弱，从而导致病毒长期持续存在。
Chronic viral infection impairs systemic immunity in the host; however, the mechanism underlying the dysfunction of immune cells in chronic viral infection is incompletely understood. In this study, we studied the lineage differentiation of hematopoietic stem cells (HSCs) during chronic viral infection to elucidate the changes in dendritic cell (DC) differentiation and subsequent impact on T cell functionality using a chronic lymphocytic choriomeningitis virus (LCMV) infection model. We first investigated the lineage differentiation of HSCs in the bone marrow (BM) to elucidate the modulation of immune cell differentiation and found that the populations highly restrained in their differentiation were common myeloid progenitors (CMPs) and common dendritic cell progenitors (CDPs). Of interest, the main immune cells infected with LCMV Clone 13 (CL13) in the BM were CD11b/c+ myeloid DCs. We next characterized CD11b+ DCs that differentiated during chronic LCMV infection. These DCs displayed a less immunogenic phenotype than DCs in naive or acutely infected mice, showing low expression of CD80 but high expression of PD-L1, B7-H4, IDO, TGF-β, and IL-10. Consequently, these CD11b+ DCs induced less effective CD8+ T cells and more Foxp3+ regulatory T (Treg) cells. Furthermore, CD11b+ DCs generated during CL13 infection could not induce effective CD8+ T cells specific to the antigens of newly invading pathogens. Our findings demonstrate that DCs generated from the BM during chronic viral infection cannot activate fully functional effector CD8+ T cells specific to newly incoming antigens as well as persistent antigens themselves, suggesting a potential cause of the functional alterations in the T cell immune response during chronic viral infection. Persistent virus infections impair the ability of the immune system’s dendritic cells to orchestrate a proper anti-pathogen defense, a finding that could lead to new treatments for chronic viral illnesses. Seungbo Yoo, Yun Hee Jeong, and Sang-Jun Ha of Yonsei University in Seoul, South Korea, and colleagues studied mice infected with lymphocytic choriomeningitis virus (LCMV), a virus carried by rodents that can cause neurological disease in humans. They showed that the virus localizes inside the bone-marrow of the animals, where it changes the way that dendritic cells form. These immunological sentinel cells normally present pieces of the viral intruder to virus-fighting T cells for them to then mount an attack. In LCMV-infected mice, the dendritic cells expressed fewer immune-stimulatory molecules and more inhibitory molecules, leading to weaker immune responses that allow for long-term viral persistence.
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DOI：
10.1084/jem.20192070
发表时间：
2021-12-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Isringhausen S;Mun Y;Kovtonyuk L;Kräutler NJ;Suessbier U;Gomariz A;Spaltro G;Helbling PM;Wong HC;Nagasawa T;Manz MG;Oxenius A;Nombela-Arrieta C
通讯作者：
Nombela-Arrieta C
影响因子：
4.4
作者：
Fuller, MJ;Zajac, AJ
通讯作者：
Zajac, AJ
影响因子：
1.2
作者：
Frascoli, Michela;Proietti, Michele;Grassi, Fabio
通讯作者：
Grassi, Fabio
影响因子：
6.4
作者：
Hassannia, Hadi;Ghasemi Chaleshtari, Mitra;Jadidi-Niaragh, Farhad
通讯作者：
Jadidi-Niaragh, Farhad
HIV-1 的细胞储存库及其在病毒持久性中的作用。
影响因子：
1
作者：
Alexaki A;Liu Y;Wigdahl B
通讯作者：
Wigdahl B