Kim Hyejin, Kimoto Takashi, Sakai Satoko, Takahashi Etsuhisa, Kido Hiroshi
Division of Enzyme Chemistry, Institute for Enzyme Research, Tokushima University, Tokushima, Japan.
PLoS One. 2018 Jan 25;13(1):e0191133. doi: 10.1371/journal.pone.0191133. eCollection 2018.
We reported previously that intranasal instillation of a synthetic human pulmonary surfactant with a carboxy vinyl polymer as a viscosity improver, named SF-10, shows potent adjuvanticity for humoral immunity in mice and cynomolgus monkeys. SF-10 effectively induces influenza hemagglutinin vaccine (HAv)-specific IgA in nasal and lung washes and IgG in sera with their neutralizing activities. Since CD8+ T cell-mediated protection is an important requirement for adaptive immunity, we investigated in this study the effects of SF-10 with antigen on local and systemic cell-mediated immunity. Nasal instillation of ovalbumin, a model antigen, combined with SF-10 efficiently delivered antigen to mucosal dendritic and epithelial cells and promoted cross-presentation in antigen presenting cells, yielding a high percentage of ovalbumin-specific cytotoxic T lymphocytes in the nasal mucosa, compared with ovalbumin alone. Nasal immunization of HAv-SF-10 also induced HAv-specific cytotoxic T lymphocytes and upregulated granzyme B expression in splenic CD8+ T cells with their high cytotoxicity against target cells pulsed with HA peptide. Furthermore, nasal vaccination of HAv-SF-10 significantly induced higher cytotoxic T lymphocytes-mediated cytotoxicity in the lungs and cervical lymph nodes in the early phase of influenza virus infection compared with HAv alone. Protective immunity induced by HAv-SF-10 against lethal influenza virus infection was partially and predominantly suppressed after depletion of CD8+ and CD4+ T cells (induced by intraperitoneal injection of the corresponding antibodies), respectively, suggesting that CD4+ T cells predominantly and CD8+ T cells partially contribute to the protective immunity in the advanced stage of influenza virus infection. These results suggest that SF-10 promotes effective antigen delivery to antigen presenting cells, activates CD8+ T cells via cross-presentation, and induces cell-mediated immune responses against antigen.
我们之前报道过，经鼻内滴注一种以羧基乙烯基聚合物作为增稠剂的合成人肺表面活性剂（名为SF-10），对小鼠和食蟹猴的体液免疫显示出强大的佐剂活性。SF-10能有效诱导流感血凝素疫苗（HAv）特异性IgA在鼻腔冲洗液和肺灌洗液中产生，以及诱导具有中和活性的血清IgG产生。由于CD8+ T细胞介导的保护作用是适应性免疫的重要条件，我们在本研究中调查了SF-10与抗原联合使用对局部和全身细胞介导免疫的影响。经鼻内滴注模型抗原卵清蛋白并联合SF-10，能有效地将抗原递送至黏膜树突状细胞和上皮细胞，并促进抗原呈递细胞中的交叉呈递，与单独使用卵清蛋白相比，在鼻黏膜中产生了高比例的卵清蛋白特异性细胞毒性T淋巴细胞。HAv-SF-10经鼻免疫也诱导了HAv特异性细胞毒性T淋巴细胞，并上调了脾CD8+ T细胞中颗粒酶B的表达，这些细胞对用HA肽脉冲处理的靶细胞具有高细胞毒性。此外，与单独使用HAv相比，在流感病毒感染早期，HAv-SF-10经鼻接种显著诱导了肺和颈部淋巴结中更高的细胞毒性T淋巴细胞介导的细胞毒性。分别在耗尽CD8+和CD4+ T细胞（通过腹腔注射相应抗体诱导）后，HAv-SF-10诱导的针对致死性流感病毒感染的保护性免疫部分且主要受到抑制，这表明在流感病毒感染后期，CD4+ T细胞起主要作用，CD8+ T细胞起部分作用。这些结果表明，SF-10促进向抗原呈递细胞有效递送抗原，通过交叉呈递激活CD8+ T细胞，并诱导针对抗原的细胞介导免疫反应。
