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J Clin Invest. 2013 September 3; 123(9): 3766–3776.
Published online 2013 August 1. doi: 10.1172/JCI66043
PMCID: PMC3754243
Mobilizing monocytes to cross-present circulating viral antigen in chronic infection
Adam J. Gehring,1 Muzlifah Haniffa,2,3 Patrick T. Kennedy,4 Zi Zong Ho,1 Carolina Boni,5 Amanda Shin,3 Nasirah Banu,1 Adeline Chia,1 Seng Gee Lim,6 Carlo Ferrari,5 Florent Ginhoux,3 and Antonio Bertoletti1,7,8
Abstract
Selection of antigens for therapeutic vaccination against chronic viral infections is complicated by pathogen genetic variations. We tested whether antigens present during persistent viral infections could provide a personalized antigenic reservoir for therapeutic T cell expansion in humans. We focused our study on the HBV surface antigen (HBsAg), which is present in microgram quantities in the serum of chronic HBV patients. We demonstrated by quantitative fluorescent microscopy that, out of 6 professional APC populations in the circulation, only CD14 monocytes (MNs) retained an HBsAg depot. Using TCR-redirected CD8+ T cells specific for MHC-I–restricted HBV epitopes, we showed that, despite being constantly exposed to antigen, ex vivo–isolated APCs did not constitutively activate HBV-specific CD8+ T cells. However, differentiation of HBsAg+ CD14 MNs from chronic patients to MN-derived DCs (moDCs) induced cross-presentation of the intracellular reservoir of viral antigen. We exploited this mechanism to cross-present circulating viral antigen and showed that moDCs from chronically infected patients stimulated expansion of autologous HBV-specific T cells. Thus, these data demonstrate that circulating viral antigen produced during chronic infection can serve as a personalized antigenic reservoir to activate virus-specific T cells.
临床研究杂志。2013年9月3;123(9):3766-3776。
2013在线发布8月1日DOI:10.1172/JCI66043
PMCID:PMC3754243
单核细胞动员循环病毒抗原交叉存在慢性感染
亚当·Gehring集团,何灾总,4,2,3帕特里克T.肯尼迪1 Muzlifah哈尼法,1卡罗莱纳博尼,5阿曼达善,巴努的Nasirah,1爱德玲嘉,1吉生林,6法拉利卡罗,5弗洛朗Ginhoux ,3和安东尼奥Bertoletti1的,7,8
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对慢性病毒感染的治疗性疫苗的抗原的选择是复杂的病原体遗传变异。我们测试了持久性病毒感染过程中存在的抗原是否能提供个性化的抗原水库治疗T细胞在人类扩张。我们集中研究对乙型肝炎病毒表面抗原(HBsAg),它是在慢性乙型肝炎患者血清中的微克数量。我们证明了定量荧光显微镜,出在流通6个专业APC人口,保留乙肝表面抗原CD14单核细胞(MNS)的车厂。特定使用TCR重定向的CD8 + T细胞的MHC-I限制性HBV抗原表位,我们发现,尽管不断暴露抗原,体外隔离装甲运兵车没有组成激活HBV特异性CD8 + T细胞。然而,诱导分化的HBsAg+ CD14牛顿从慢性病患者来自MN-DCS(moDCs)交叉呈递病毒抗原的细胞内储。利用此机制,以交叉本循环病毒抗原,并表明从慢性感染患者或MoDCs刺激自体的HBV特异性T细胞的扩大。因此,这些数据表明,循环过程中产生的慢性感染的病毒抗原可作为个性化的病毒激活特异性T细胞的抗原储层。 |
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