Aberle Judith H, Schwaiger Julia, Aberle Stephan W, Stiasny Karin, Scheinost Ondrej, Kundi Michael, Chmelik Vaclav, Heinz Franz X
Department of Virology, Medical University of Vienna, Vienna, Austria.
Laboratory of Molecular Genetics, Hospital České Budĕjovice, České Budĕjovice, Czech Republic.
PLoS One. 2015 Oct 14;10(10):e0140545. doi: 10.1371/journal.pone.0140545. eCollection 2015.
Tick-borne encephalitis virus (TBEV) is a human-pathogenic flavivirus that is endemic in large parts of Europe and Asia and causes severe neuroinvasive illness. A formalin-inactivated vaccine induces strong neutralizing antibody responses and confers protection from TBE disease. CD4+ T cell responses are essential for neutralizing antibody production, but data on the functionalities of TBEV-specific CD4+ T cells in response to vaccination or infection are lacking. This study provides a comprehensive analysis of the cytokine patterns of CD4+ T cell responses in 20 humans after TBE vaccination in comparison to those in 18 patients with TBEV infection. Specifically, Th1-specific cytokines (IFN-γ, IL-2, TNF-α), CD40 ligand and the Th1 lineage-specifying transcription factor Tbet were determined upon stimulation with peptides covering the TBEV structural proteins contained in the vaccine (C-capsid, prM/M-membrane and E-envelope). We show that TBEV-specific CD4+ T cell responses are polyfunctional, but the cytokine patterns after vaccination differed from those after infection. TBE vaccine responses were characterized by lower IFN-γ responses and high proportions of TNF-α+IL-2+ cells. In vaccine-induced responses-consistent with the reduced IFN-γ expression patterns-less than 50% of TBEV peptides were detected by IFN-γ+ cells as compared to 96% detected by IL-2+ cells, indicating that the single use of IFN-γ as a read-out strongly underestimates the magnitude and breadth of such responses. The results provide important insights into the functionalities of CD4+ T cells that coordinate vaccine responses and have direct implications for future studies that address epitope specificity and breadth of these responses.
蜱传脑炎病毒（TBEV）是一种可感染人类的黄病毒，在欧洲和亚洲大部分地区流行，可引发严重的神经侵袭性疾病。一种福尔马林灭活疫苗可诱导强烈的中和抗体反应，并提供对蜱传脑炎的保护。CD4 + T细胞反应对于中和抗体的产生至关重要，但缺乏关于TBEV特异性CD4 + T细胞在疫苗接种或感染后的功能数据。本研究全面分析了20名人类接种TBE疫苗后与18名TBEV感染患者相比，CD4 + T细胞反应的细胞因子模式。具体而言，在用覆盖疫苗中包含的TBEV结构蛋白（C-衣壳、prM/M-膜和E-包膜）的肽刺激后，测定了Th1特异性细胞因子（IFN-γ、IL-2、TNF-α）、CD40配体和Th1谱系特异性转录因子Tbet。我们表明，TBEV特异性CD4 + T细胞反应具有多功能性，但疫苗接种后的细胞因子模式与感染后的不同。TBE疫苗反应的特征是IFN-γ反应较低，TNF-α+IL-2 +细胞比例较高。在疫苗诱导的反应中——与IFN-γ表达模式降低一致——IFN-γ+细胞检测到的TBEV肽不到50%，而IL-2 +细胞检测到的为96%，这表明仅使用IFN-γ作为读数会严重低估此类反应的幅度和广度。这些结果为协调疫苗反应的CD4 + T细胞功能提供了重要见解，并对未来研究这些反应的表位特异性和广度具有直接影响。
