Vaginal memory T cells induced by intranasal vaccination are critical for protective T cell recruitment and prevention of genital HSV-2 disease.
Vaginal memory T cells induced by intranasal vaccination are critical for protective T cell recruitment and prevention of genital HSV-2 disease.
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鼻内疫苗接种诱导的阴道记忆 T 细胞对于保护性 T 细胞募集和预防生殖器 HSV-2 疾病至关重要。
DOI：
10.1128/jvi.02279-14
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
H.
中科院分区：
文献类型：
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作者：
Sato;A.;Suwanto;A.;Okabe;M.;Sato;S.;Nochi;T.;Imai;T.;Koyanagi;N.;Kunisawa;J.;Kawaguchi;Y. and Kiyono;H.
针对引起慢性感染的生殖器病原体的保护性免疫，如单纯疱疹病毒2型（HSV-2）或人类免疫缺陷病毒，需要在生殖道局部诱导细胞介导的免疫反应。胸苷激酶缺陷（TK -）突变型HSV-2鼻内免疫可有效诱导HSV-2特异性γ干扰素（IFN-γ）分泌记忆T细胞的产生，并对野生型HSV-2阴道内攻击产生保护性免疫。然而，鼻内免疫比全身免疫更有效地诱导远端生殖器粘膜保护性免疫的确切机制尚不清楚。在这里，我们发现用活的HSV-2 TK -鼻内免疫诱导了效应T细胞的产生，并将其迁移到阴道粘膜中，而全身疫苗接种几乎不能建立局部效应T细胞库，即使它诱导了循环记忆T细胞在全身腔室的产生。鼻内疫苗接种诱导的持久的HSV-2特异性局部效应T细胞比腹腔免疫接种更早地在进入部位开始病毒清除，从而对阴道内野生型HSV-2攻击提供了更好的保护。鼻内免疫是一种有效的策略，通过提供持久的抗原（Ag）特异性局部效应T细胞而不引起局部感染或炎症，从而激发高水平的细胞介导的生殖道保护。预防由单纯疱疹病毒2型（HSV-2）等病毒引起的性传播疾病的鼻内疫苗一直在开发中，但目前尚无候选疫苗可用。了解单纯疱疹病毒2型免疫诱导远端阴道黏膜免疫应答的细胞机制将有助于设计这种疫苗。我们的研究表明，与全身免疫相比，用HSV-2减毒株免疫在阴道粘膜中产生长效分泌IFN-γ的T细胞更有效。我们发现这些阴道效应记忆T细胞对自然感染部位的早期病毒清除至关重要，并预防严重的阴道炎症和疱疹性脑炎。
Protective immunity against genital pathogens causing chronic infections, such as herpes simplex virus 2 (HSV-2) or human immunodeficiency virus, requires the induction of cell-mediated immune responses locally in the genital tract. Intranasal immunization with a thymidine kinase-deficient (TK−) mutant of HSV-2 effectively induces HSV-2-specific gamma interferon (IFN-γ)-secreting memory T cell production and protective immunity against intravaginal challenge with wild-type HSV-2. However, the precise mechanism by which intranasal immunization induces protective immunity in the distant genital mucosa more effectively than does systemic immunization is unknown. Here, we showed that intranasal immunization with live HSV-2 TK−induced the production of effector T cells and their migration to, and retention in, the vaginal mucosa, whereas systemic vaccination barely established a local effector T cell pool, even when it induced the production of circulating memory T cells in the systemic compartment. The long-lasting HSV-2-specific local effector T cells induced by intranasal vaccination provided superior protection against intravaginal wild-type HSV-2 challenge by starting viral clearance at the entry site earlier than with intraperitoneal immunization. Intranasal immunization is an effective strategy for eliciting high levels of cell-mediated protection of the genital tract by providing long-lasting antigen (Ag)-specific local effector T cells without introducing topical infection or inflammation.IMPORTANCEIntranasal (i.n.) vaccines against sexually transmitted diseases that are caused by viruses such as herpes simplex virus 2 (HSV-2) have long been in development, but no vaccine candidate is currently available. Understanding the cellular mechanisms of immune responses in a distant vaginal mucosa induced by i.n. immunization with HSV-2 will contribute to designing such a vaccine. Our study demonstrated that i.n. immunization with an attenuated strain of HSV-2 generated long-lasting IFN-γ-secreting T cells in vaginal mucosa more effectively than systemic immunization. We found that these vaginal effector memory T cells are critical for the early stage of viral clearance at natural infection sites and prevent severe vaginal inflammation and herpes encephalitis.