Effective Respiratory CD8 T-Cell Immunity to Influenza Virus Induced by Intranasal Carbomer-Lecithin-Adjuvanted Non-replicating Vaccines.
Effective Respiratory CD8 T-Cell Immunity to Influenza Virus Induced by Intranasal Carbomer-Lecithin-Adjuvanted Non-replicating Vaccines.
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DOI：
10.1371/journal.ppat.1006064
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发表时间：
2016-12
期刊：
影响因子：
6.7
通讯作者：
Suresh M
中科院分区：
文献类型：
--
作者：
Gasper DJ;Neldner B;Plisch EH;Rustom H;Carrow E;Imai H;Kawaoka Y;Suresh M
CD8+ 细胞毒性 T 淋巴细胞 (CTL) 对于清除许多病毒感染至关重要，并且可以通过接种减毒病毒和载体来诱导保护性 CTL 记忆。非复制疫苗通常通过添加增强体液反应的佐剂来增强效果，但很少能够产生 CTL 反应。 Adjuplex 是一种基于卡波姆-卵磷脂的佐剂，经证明可引发针对非复制抗原的强大体液免疫。我们报告说，用非复制型 Adjuplex 佐剂疫苗免疫的小鼠产生了强烈的抗原特异性 CTL 反应。皮下或鼻内途径的疫苗接种分别刺激全身和粘膜CTL记忆。然而，只有鼻内疫苗接种诱导的 CTL 记忆才能抵抗流感病毒的攻击，并且与气道中记忆 CTL 和肺部 CD103+ CD69+ CXCR3+ 常驻记忆样 CTL 的增强相关。从机制上讲，Myd88 缺陷小鼠对 Adjuplex 疫苗产生初级 CTL 反应，其程度与野生型小鼠相似，但表现出效应细胞亚群分化的改变。 Adjuplex 的免疫增强作用导致疫苗引流淋巴结以及鼻内疫苗接种后肺部和气道中抗原呈递细胞亚群频率的改变。此外，Adjuplex 通过调节抗原摄取、细胞内定位和加工速率，增强了树突状细胞促进抗原诱导的幼稚 CD8 T 细胞增殖的能力。总之，我们发现了一种佐剂，它能引发对非复制抗原的全身和粘膜 CTL 记忆，并在呼吸道中产生针对甲型流感病毒的基于 CTL 的异亚型保护性免疫。此外，本手稿中提出的研究结果为控制呼吸道中系统性和保护性记忆 CTL 的诱导和编程的机制和因素提供了重要见解。目前的呼吸道病毒疫苗通常采用非复制抗原并仅依靠体液反应的产生来提供保护。流感等病毒可以变异并逃避这些反应，从而限制免疫力并需要重新接种疫苗。细胞介导的免疫 (CMI) 可以通过针对不经常突变的病毒成分来提供更广泛的保护，但目前还没有能够诱导 CMI 的非复制疫苗。疫苗开发的障碍包括对保护性呼吸道 CMI 性质的不完全了解以及缺乏能够引发非复制抗原 CMI 的疫苗佐剂。使用小鼠模型，我们表征了 CMI 对用佐剂 Adjuplex 配制的非复制疫苗的反应所提供的保护性免疫。我们发现通过皮下或鼻内途径接种疫苗能够诱导有效的 CMI 反应。然而，只有鼻内疫苗接种才能防止异亚型流感病毒的攻击。这种保护作用与肺部具有常驻记忆表型的 T 细胞的增强相关。此外，机制研究表明，Adjuplex 通过激活和改变抗原摄取、加工和呈递来影响抗原呈递细胞。目前的研究：（1）鉴定出一种佐剂，可引发对呼吸道病毒病原体的保护性CMI； (2)表明刺激呼吸道中的保护性CMI需要鼻内疫苗递送。
CD8+ cytotoxic T lymphocytes (CTLs) are critical for clearing many viral infections, and protective CTL memory can be induced by vaccination with attenuated viruses and vectors. Non-replicating vaccines are typically potentiated by the addition of adjuvants that enhance humoral responses, however few are capable of generating CTL responses. Adjuplex is a carbomer-lecithin-based adjuvant demonstrated to elicit robust humoral immunity to non-replicating antigens. We report that mice immunized with non-replicating Adjuplex-adjuvanted vaccines generated robust antigen-specific CTL responses. Vaccination by the subcutaneous or the intranasal route stimulated systemic and mucosal CTL memory respectively. However, only CTL memory induced by intranasal vaccination was protective against influenza viral challenge, and correlated with an enhancement of memory CTLs in the airways and CD103+ CD69+ CXCR3+ resident memory-like CTLs in the lungs. Mechanistically, Myd88-deficient mice mounted primary CTL responses to Adjuplex vaccines that were similar in magnitude to wild-type mice, but exhibited altered differentiation of effector cell subsets. Immune potentiating effects of Adjuplex entailed alterations in the frequency of antigen-presenting-cell subsets in vaccine draining lymph nodes, and in the lungs and airways following intranasal vaccination. Further, Adjuplex enhanced the ability of dendritic cells to promote antigen-induced proliferation of naïve CD8 T cells by modulating antigen uptake, its intracellular localization, and rate of processing. Taken together, we have identified an adjuvant that elicits both systemic and mucosal CTL memory to non-replicating antigens, and engenders protective CTL-based heterosubtypic immunity to influenza A virus in the respiratory tract. Further, findings presented in this manuscript have provided key insights into the mechanisms and factors that govern the induction and programming of systemic and protective memory CTLs in the respiratory tract. Current respiratory-virus vaccines typically employ non-replicating antigens and rely solely on the generation of humoral responses for protection. Viruses such as influenza can mutate and escape these responses, thereby limiting immunity and necessitating revaccination. Cell-mediated immunity (CMI) could provide broader protection by targeting viral components that infrequently mutate, however non-replicating vaccines capable of inducing CMI are not available. Impediments to vaccine development include an incomplete understanding of the nature of protective respiratory CMI and a lack of vaccine adjuvants capable of eliciting CMI to non-replicating antigens. Using a mouse model, we characterized the protective immunity afforded by CMI responses to non-replicating vaccines formulated with the adjuvant Adjuplex. We found that vaccination via either the subcutaneous or intranasal route was capable of inducing potent CMI responses. However, only intranasal vaccination protected against challenge with heterosubtypic influenza viruses. This protection correlated with enhancement of T cells with a resident-memory phenotype in the lungs. Additionally, mechanistic studies showed that Adjuplex affects antigen-presenting cells via activation and alteration of antigen uptake, processing, and presentation. The current studies: (1) identified an adjuvant that elicits protective CMI to respiratory viral pathogens; (2) suggested that stimulation of protective CMI in the respiratory tract requires intranasal vaccine delivery.
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