Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses
Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses
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DOI：
10.1172/jci63287
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发表时间：
2012-12-01
影响因子：
15.9
通讯作者：
Schiller, John T.
中科院分区：
文献类型：
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作者：
Cuburu, Nicolas;Graham, Barney S.;Schiller, John T.
诱导持续的上皮内CD8(+) T细胞反应可能是开发针对粘膜传播病原体（特别是性传播疾病）的疫苗的关键；本文研究了人乳头瘤病毒载体（HPV假病毒）在宫颈阴道角质形成细胞中短暂表达一种模型抗原——呼吸道合胞病毒（RSV） M/M2，经阴道内免疫后，雌性小鼠宫颈阴道粘膜CD8(+) T细胞的应答。不同HPV血清型的HPV阴道内启动/增强诱导的宫颈抗原特异性CD8(+) T细胞数量是单独启动的10倍，6个月后抗原特异性T细胞数量仅下降2倍。大多数生殖器抗原特异性CD8(+) T细胞位于上皮内或上皮下，表达α (E)-整合素CD103，产生ifn - γ和tnf - α，并表现出体内细胞毒性。使用鞘鞘醇-l-磷酸类似物（FTY720），我们发现在HPV阴道内刺激后，启动的CD8(+) T细胞在宫颈阴道黏膜中增殖。在表达CD8表位M2的牛痘病毒阴道内攻击后，阴道内HPV启动/增强使宫颈阴道病毒滴度降低了1000倍。相比之下，腺病毒5型载体的肌内启动/增强诱导了更高水平的全身CD8(+) T细胞，但未能诱导上皮内CD103(+)CD8(+) T细胞或防止重组痘苗阴道攻击。因此，HPV载体是有吸引力的基因传递平台，通过促进引物抗原特异性CD8(+) T细胞的局部增殖和保留，诱导持久的宫颈阴道上皮内CD8(+) T细胞反应。
The induction of persistent intraepithelial CD8(+) T cell responses may be key to the development of Vaccines against mucosally transmitted pathogens, particularly for sexually transmitted diseases; Here we investigated CD8(+) T cell responses in the female mouse cervicovaginal mucosa after intravaginal immunization with human papillomavirus vectors (HPV pseudoviruses) that transiently expressed a model antigen, respiratory syncytial virus (RSV) M/M2, in cervicovaginal keratinocytes. An HPV intravaginal prime/boost with different HPV serotypes induced 10 fold more cervicovaginal antigen specific CD8(+) T cells than priming alone Antigen specific T cell numbers decreased only 2-fold after 6 months. Most genital antigen specific CD8(+), T cells were intra- or subepithelial, expressed alpha(E)-integrin CD103, produced IFN-gamma and TNF-alpha, and displayed in vivo cytotoxicity. Using a sphingosine-l-phosphate analog (FTY720), we found that the primed CD8(+) T cells proliferated in the cervicovaginal mucosa upon HPV intravaginal boost Intravaginal HPV prime/boost reduced cervicovaginal viral titers 1,000 fold after intravaginal challenge with vaccinia virus expressing the CD8 epitope M2. In contrast, intramuscular prime/boost with an adenovirus type 5 vector induced a higher level of systemic CD8(+) T cells but failed to induce intraepithelial CD103(+)CD8(+) T cells or protect against recombinant vaccinia vaginal challenge. Thus, HPV vectors are attractive gene-delivery platforms for inducing durable intraepithelial cervicovaginal CD8(+) T cell responses by promoting local proliferation and retention of primed antigen specific CD8(+) T cells.