Quality of the Transgene-Specific CD8+ T Cell Response Induced by Adenoviral Vector Immunization Is Critically Influenced by Virus Dose and Route of Vaccination
Quality of the Transgene-Specific CD8+ T Cell Response Induced by Adenoviral Vector Immunization Is Critically Influenced by Virus Dose and Route of Vaccination
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DOI：
10.4049/jimmunol.0900537
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发表时间：
2010-04-15
影响因子：
4.4
通讯作者：
Christensen, Jan Pravsgaard
中科院分区：
文献类型：
--
作者：
Holst, Peter Johannes;Orskov, Cathrine;Christensen, Jan Pravsgaard
腺病毒载体已被广泛用于实验性基因治疗和疫苗接种，但令人惊讶的是缺乏知识连接的途径和剂量的腺病毒管理诱导的转基因特异性免疫应答。我们最近使用腺病毒载体证明了多功能的CD 8（+）T细胞和保护性记忆应答，这似乎与最近的报告形成对比，该报告表明，通过接种腺病毒载体诱导耗尽的CD 8（+）T细胞表型。因此，我们研究了使用编码β-半乳糖苷酶的腺病毒载体的转基因特异性CD 8（+）T细胞的途径和剂量相互关系，无论接种途径如何，当剂量增加超过1 e颗粒时，发现大多数腺病毒接种物全身性传播。转基因特异性CD 8（+）T细胞的数量与传播呈正相关，而产生的T细胞的功能能力与载体传播呈负相关。对s.c.或静脉注射中等剂量给药后发现，通过两种途径接种均诱导产生IFN-γ的CD 8（+）T细胞在感染后2至3周出现短暂高峰，但静脉注射给药后，仅在肝脏中检测到这些细胞。全身免疫后2 - 4个月，而非外周免疫后，功能障碍的转基因特异性CD 8（+）T细胞在脾脏中积聚，这些细胞因子产生和重要的体内效应器功能均受损。这些发现表明腺病毒接种物的定位而不是总Ag载量决定了腺病毒疫苗诱导的CD 8（+）T细胞应答的质量。免疫学杂志，2010，184：4431-4439。
Adenoviral vectors have been widely used for experimental gene therapy and vaccination, yet there is a surprising lack of knowledge connecting the route and dose of adenovirus administration to the induced transgene-specific immune response. We have recently demonstrated polyfunctional CD8(+) T cells and protective memory responses using adenoviral vectors, which seem to contrast with recent reports suggesting that an exhausted CD8(+) T cell phenotype is induced by inoculation with adenoviral vectors. Accordingly, we investigated the route and dose interrelationship for transgene-specific CD8(+) T cells using adenoviral vectors encoding beta-galactosidase applied either s.c. or i.v. Irrespective of the route of inoculation, most of the adenoviral inoculum was found to disseminate systemically as the dose was raised beyond le particles. The number of transgene-specific CD8(+) T cells correlated positively with dissemination, whereas the functional capacity of the generated T cells correlated inversely with vector dissemination. A comparison of the immune response to s.c. or i.v. administration at moderate doses revealed that inoculation by both routes induced a transient peak of IFN-gamma-producing CD8(+) T cells 2 to 3 wk postinfection, but following i.v. administration, these cells were only detected in the liver. Two to four months after systemic, but not peripheral, immunization, dysfunctional transgene-specific CD8(+) T cells impaired in both cytokine production and important in vivo effector functions, accumulated in the spleen. These findings indicate that the localization of the adenoviral inoculum and not the total Ag load determines the quality of the CD8(+) T cell response induced with adenoviral vaccines. The Journal of Immunology, 2010, 184: 4431-4439.