Protective Regulatory T Cell Immune Response Induced by Intranasal Immunization With the Live-Attenuated Pneumococcal Vaccine SPY1 via the Transforming Growth Factor-β1-Smad2/3 Pathway.
Protective Regulatory T Cell Immune Response Induced by Intranasal Immunization With the Live-Attenuated Pneumococcal Vaccine SPY1 via the Transforming Growth Factor-β1-Smad2/3 Pathway.
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肺炎球菌减毒活疫苗 SPY1 通过转化生长因子-β 1-Smad2/3 途径鼻内免疫诱导的保护性调节 T 细胞免疫反应
DOI：
10.3389/fimmu.2018.01754
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发表时间：
2018
影响因子：
7.3
通讯作者：
Xu X
中科院分区：
文献类型：
--
作者：
Liao H;Peng X;Gan L;Feng J;Gao Y;Yang S;Hu X;Zhang L;Yin Y;Wang H;Xu X
疫苗的有效性主要取决于其介导保护的机制，强调了揭示肺炎球菌新型疫苗的保护机制的重要性。我们之前证明了调节性T细胞（Treg）免疫应答对由肺炎球菌减毒活疫苗SPY1引起的肺炎球菌感染具有保护作用。然而，这种保护作用的机制尚不清楚。在这项研究中，一种短合成肽（P17）在小鼠模型免疫和随后的挑战中下调Tregs。在免疫小鼠中，经P17处理后，SPY1诱导的免疫细胞因子（IL-12p70、IL-4、IL-5和IL-17A）的升高进一步上调，而SPY1诱导的感染相关炎症细胞因子TNF-α的降低被逆转。P17还抑制免疫小鼠免疫抑制细胞因子IL-10和炎症介质IL-6的增加。在p17免疫小鼠中，更严重的肺损伤和更剧烈的炎症反应以及更差的生存表明Treg免疫反应通过维持SPY1刺激的获得性免疫反应之间的平衡，在预防肺炎球菌感染方面发挥了不可或缺的作用。进一步的研究表明，SPY1疫苗显著升高活性转化生长因子β (TGF-β)1激活FOXP3，导致CD4+CD25+ FOXP3 + T细胞的频率增加。此外，在肺炎球菌感染期间，SPY1疫苗接种以时间依赖性的方式提高了Smad2/3和磷酸化Smad2/3的水平，并下调了负调节因子Smad7的水平，而这些变化被P17治疗逆转。这些结果表明，spy1刺激的TGF-β1通过Smad2/3信号通路诱导spy1特异性Tregs的产生。此外，spy1特异性Tregs可能通过增强PD-1和CTLA-4的表达参与保护。本文提供的数据扩展了我们对spy1诱导的获得性Treg免疫反应如何促进减毒活疫苗的保护的理解，并可能有助于活疫苗和其他粘膜候选疫苗的评估。
Vaccine effectiveness is mainly determined by the mechanism mediating protection, emphasizing the importance of unraveling the protective mechanism for novel pneumococcal vaccine development. We previously demonstrated that the regulatory T cell (Treg) immune response has a protective effect against pneumococcal infection elicited by the live-attenuated pneumococcal vaccine SPY1. However, the mechanism underlying this protective effect remains unclear. In this study, a short synthetic peptide (P17) was used to downregulate Tregs during immunization and subsequent challenges in a mouse model. In immunized mice, increase in immune cytokines (IL-12p70, IL-4, IL-5, and IL-17A) induced by SPY1 were further upregulated by P17 treatment, whereas the decrease in the infection-associated inflammatory cytokine TNF-α by SPY1 was reversed. P17 also inhibited the increase in the immunosuppressive cytokine IL-10 and inflammatory mediator IL-6 in immunized mice. More severe pulmonary injuries and more dramatic inflammatory responses with worse survival in P17-treated immunized mice indicated the indispensable role of the Treg immune response in protection against pneumococcal infection by maintaining a balance among acquired immune responses stimulated by SPY1. Further studies revealed that the significant elevation of active transforming growth factor β (TGF-β)1 by SPY1 vaccination activated FOXP3, leading to increased frequencies of CD4+CD25+Foxp3+ T cells. Moreover, SPY1 vaccination elevated the levels of Smad2/3 and phosphor-Smad2/3 and downregulated the negative regulatory factor Smad7 in a time-dependent manner during pneumococcal infection, and these changes were reversed by P17 treatment. These results illustrate that SPY1-stimulated TGF-β1 induced the generation of SPY1-specific Tregs via the Smad2/3 signaling pathway. In addition, SPY1-specific Tregs may participate in protection via the enhanced expression of PD-1 and CTLA-4. The data presented here extend our understanding of how the SPY1-induced acquired Treg immune response contributes to protection elicited by live-attenuated vaccines and may be helpful for the evaluation of live vaccines and other mucosal vaccine candidates.
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影响因子：
15.3
作者：
Fahlén, L;Read, S;Gorelik, L;Hurst, SD;Coffman, RL;Flavell, RA;Powrie, F
通讯作者：
Powrie, F
DOI：
10.4049/jimmunol.1000423
发表时间：
2010-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fulton RB;Meyerholz DK;Varga SM
通讯作者：
Varga SM
影响因子：
3.7
作者：
Huber S;Schrader J;Fritz G;Presser K;Schmitt S;Waisman A;Lüth S;Blessing M;Herkel J;Schramm C
通讯作者：
Schramm C
影响因子：
32.4
作者：
Li, Ming O.;Wan, Yisong Y.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
DOI：
10.1073/pnas.0910341107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Jain, Nitya;Nguyen, Hai;Kang, Joonsoo
通讯作者：
Kang, Joonsoo