Mobilizing monocytes to cross-present circulating viral antigen in chronic infection
Mobilizing monocytes to cross-present circulating viral antigen in chronic infection
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DOI：
10.1172/jci66043
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发表时间：
2013-09-01
影响因子：
15.9
通讯作者：
Bertoletti, Antonio
中科院分区：
文献类型：
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作者：
Gehring, Adam J.;Haniffa, Muzlifah;Bertoletti, Antonio
针对慢性病毒感染的治疗性疫苗接种的抗原选择因病原体遗传变异而复杂化。我们测试了持续性病毒感染期间存在的抗原是否可以为人类治疗性T细胞扩增提供个性化的抗原库。我们的研究集中在HBV表面抗原（HBsAg），这是目前在慢性HBV患者血清中的微克数量。我们通过定量荧光显微镜证实，在循环中的6个专业APC群体中，只有CD 14单核细胞（MN）保留HBsAg库。使用TCR重定向的CD 8（+）T细胞特异性的MHC-I限制性HBV表位，我们发现，尽管不断暴露于抗原，体外分离的APC不能组成性激活HBV特异性CD 8（+）T细胞。然而，来自慢性患者的HBsAg（+）CD 14 MN分化为MN衍生的DC（moDC）诱导了病毒抗原的细胞内储库的交叉呈递。我们利用这种机制交叉呈递循环病毒抗原，并表明来自慢性感染患者的moDCs刺激自体HBV特异性T细胞的扩增。因此，这些数据表明，在慢性感染过程中产生的循环病毒抗原可以作为一个个性化的抗原库，以激活病毒特异性T细胞。
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.