Toll-like receptor 7 controls the anti-retroviral germinal center response.
Toll-like receptor 7 controls the anti-retroviral germinal center response.
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DOI：
10.1371/journal.ppat.1002293
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发表时间：
2011-10
期刊：
影响因子：
6.7
通讯作者：
Browne EP
中科院分区：
文献类型：
--
作者：
Browne EP
开发能够增强对病毒病原体免疫力的疫苗是一个重要目标。然而，调节免疫反应强度和质量的先天分子途径在很大程度上仍然未知。为了确定 Toll 样受体 (TLR) 信号传导在控制模型逆转录病毒病原体 Friend 病毒 (FV) 中的作用，我培育了小鼠，其中树突状细胞 (DC) 或 B 细胞谱系中的 TLR 信号传导适配器 Myd88 被选择性删除。 DC中Myd88的删除对FV的免疫控制影响不大，而B细胞特异性删除Myd88导致病毒感染中心急剧增加和抗体反应显着降低，表明B细胞固有的TLR信号传导起着至关重要的作用，而DC中的TLR信号传导则不太重要。然后，我通过分析 TLR7 缺陷的小鼠，确定了单链 RNA 传感蛋白 TLR7 是抗体介导的 FV 控制所必需的。值得注意的是，受感染的 TLR7 缺陷小鼠的 B 细胞在感染早期上调 CD69 和 CD86，但未能发育成生发中心 B 细胞。在 TLR7 缺失的情况下，CD4 T 细胞反应也会减弱，但 CD8 反应与 TLR7 无关，表明存在检测逆转录病毒颗粒的其他途径。这些结果共同表明，脊椎动物免疫系统通过 TLR7 检测体内逆转录病毒，并且该途径调节控制生发中心 B 细胞发育的关键检查点。病毒感染会引发有效的病原体特异性免疫反应，其中涉及中和病毒颗粒的抗体和直接杀死感染细胞的 CD8 T 细胞。疫苗也会引发免疫反应，但目前针对 HIV-1 等逆转录病毒的疫苗还不够。定义调节这种反应的基因和途径将确定新的治疗靶点，从而增强对感染或预防性疫苗的免疫反应。利用小鼠遗传学，我证明了宿主蛋白 Toll 样受体七 (TLR7) 可以识别逆转录病毒并调节抗体对感染的反应。 TLR7 是检测微生物并引发炎症的古老基因家族的成员，但其在抗体反应中的作用尚未明确定义。我发现 TLR7 控制抗体反应中的一个特定步骤，称为生发中心反应。生发中心调节防止病毒感染的抗体的发育，操纵 B 细胞中的 TLR7 及其信号通路可能是增强病毒免疫力的可行策略。
The development of vaccines that can enhance immunity to viral pathogens is an important goal. However, the innate molecular pathways that regulate the strength and quality of the immune response remain largely uncharacterized. To define the role of Toll-like receptor (TLR) signaling in control of a model retroviral pathogen, Friend virus (FV), I generated mice in which the TLR signaling adapter Myd88 was selectively deleted in dendritic cell (DC) or in B cell lineages. Deletion of Myd88 in DCs had little effect on immune control of FV, while B cell specific deletion of Myd88 caused a dramatic increase in viral infectious centers and a significantly reduced antibody response, indicating that B cell-intrinsic TLR signaling plays a crucial role, while TLR signaling in DCs is less important. I then identified the single-stranded RNA sensing protein TLR7 as being required for antibody-mediated control of FV by analyzing mice deficient in TLR7. Remarkably, B cells in infected TLR7-deficient mice upregulated CD69 and CD86 early in infection, but failed to develop into germinal center B cells. CD4 T cell responses were also attenuated in the absence of TLR7, but CD8 responses were TLR7 independent, suggesting the existence of additional pathways for detection of retroviral particles. Together these results demonstrate that the vertebrate immune system detects retroviruses in vivo via TLR7 and that this pathway regulates a key checkpoint controlling development of germinal center B cells. Viral infection triggers potent pathogen-specific immune responses involving antibodies that neutralize viral particles and CD8 T cells that directly kill infected cells. Vaccines also trigger immune responses, but current vaccines for retroviruses such as HIV-1, are inadequate. Defining the genes and pathways that regulate this response will identify new targets for therapies that can enhance the immune response to infection or to prophylactic vaccines. Using mouse genetics, I have demonstrated that a host protein, Toll-like receptor seven (TLR7) recognizes retroviruses and regulates the antibody response to infection. TLR7 is a member of an ancient family of genes that detect microbes and initiate inflammation, but its role in antibody responses has not been clearly defined. I have discovered that TLR7 controls a specific step in the antibody response called the germinal center reaction. Germinal centers regulate the development of antibodies that protect against viral infection, and manipulation of TLR7 and its signaling pathway in B cells could be a viable strategy for enhancing immunity to viruses.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
影响因子：
32.4
作者：
Hou B;Saudan P;Ott G;Wheeler ML;Ji M;Kuzmich L;Lee LM;Coffman RL;Bachmann MF;DeFranco AL
通讯作者：
DeFranco AL
影响因子：
32.4
作者：
Hou, Baidong;Reizis, Boris;DeFranco, Anthony L.
通讯作者：
DeFranco, Anthony L.
影响因子：
56.9
作者：
BARRESINOUSSI, F;CHERMANN, JC;MONTAGNIER, L
通讯作者：
MONTAGNIER, L
DOI：
10.1073/pnas.0909545106
发表时间：
2009-10-20
影响因子：
11.1
作者：
Choi, Myoung Kwon;Wang, ZhiChao;Taniguchi, Tadatsugu
通讯作者：
Taniguchi, Tadatsugu