Combined mTOR Inhibition and OX40 Agonism Enhances CD8+ T Cell Memory and Protective Immunity Produced by Recombinant Adenovirus Vaccines
Combined mTOR Inhibition and OX40 Agonism Enhances CD8+ T Cell Memory and Protective Immunity Produced by Recombinant Adenovirus Vaccines
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DOI：
10.1038/mt.2011.281
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发表时间：
2012-04-01
影响因子：
12.4
通讯作者：
Bramson, Jonathan L.
中科院分区：
文献类型：
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作者：
Bassett, Jennifer D.;Swift, Stephanie L.;Bramson, Jonathan L.
重组人腺病毒血清型5(RHuAd5)疫苗免疫后产生的记忆CD8(+)T细胞群主要由功能有限的效应细胞和效应记忆细胞(T-EM)组成。在这项研究中，我们研究了免疫调节剂治疗是否可以增强和/或重新分配由rHuAd5引起的CD8(+)记忆群体。联合接种雷帕霉素(以调节分化)和OX40激动剂(以增强共刺激)可增加CD8(+)记忆T细胞群体的数量和多功能性，并扩大T-EM和记忆前体群体。此外，这一干预措施加强了对多种病毒挑战的保护。需要减弱腺病毒转基因表达才能使雷帕霉素+OX40激动剂联合免疫调节治疗进一步增强向中央记忆形成的倾斜，表明抗原持续表达最终限制了rHuAd5免疫后该记忆群体的发展。这些结果表明，在腺病毒免疫后的扩增阶段，哺乳动物雷帕霉素靶标(MTOR)活性的水平、共刺激量和抗原可获得性的持续时间共同决定了记忆性CD8(+)T细胞的数量、表型和功能。这些因素的调制可用于选择性地操纵记忆形成。
The memory CD8(+) T cell population elicited by immunization with recombinant human adenovirus serotype 5 (rHuAd5) vaccines is composed primarily of effector and effector memory cells (T-EM) with limited polyfunctionality. In this study, we investigated whether treatment with immunomodulators could enhance and/or redistribute the CD8(+) memory population elicited by rHuAd5. Vaccination in combination with both rapamycin (to modulate differentiation) and an OX40 agonist (to enhance costimulation) increased both the quantity and polyfunctionality of the CD8(+) memory T cell population, with expansion of the T-EM and memory precursor populations. Furthermore, this intervention enhanced protection against multiple virus challenges. Attenuation of adenovirus transgene expression was required to enable the combination rapamycin + OX40 agonist immunomodulatory treatment to further enhance skewing towards central memory formation, indicating that persistence of antigen expression ultimately limits development of this memory population following rHuAd5 immunization. These results demonstrate that during the expansion phase following adenovirus immunization, the level of mammalian target of rapamycin (mTOR) activity, the amount of costimulation and the duration of antigen availability act together to define the magnitude, phenotype, and functionality of memory CD8(+) T cells. Modulation of these factors can be used to selectively manipulate memory formation.