Department of Infectious Diseases, Leiden University Medical Center , Leiden , Netherlands.
Front Immunol. 2014 Jun 25;5:256. doi: 10.3389/fimmu.2014.00256. eCollection 2014.
In view of the fact that only a small part of the Mtb expressome has been explored for identification of antigens capable of activating human T-cell responses, which is critically required for the design of better TB vaccination strategies, more emphasis should be placed on innovative ways to discover new Mtb antigens and explore their function at the several stages of infection. Better protective antigens for TB-vaccines are urgently needed, also in view of the disappointing results of the MVA85 vaccine, which failed to induce additional protection in BCG-vaccinated infants (1). Moreover, immune responses to relevant antigens may be useful to identify TB-specific biomarker signatures. Here, we describe the potency of novel tools and strategies to reveal such Mtb antigens. Using proteins specific for different Mtb infection phases, many new antigens of the latency-associated Mtb DosR-regulon as well as resuscitation promoting factor proteins, associated with resuscitating TB, were discovered that were recognized by CD4(+) and CD8(+) T-cells. Furthermore, by employing MHC binding algorithms and bioinformatics combined with high-throughput human T-cell screens and tetramers, HLA-class Ia restricted polyfunctional CD8(+) T-cells were identified in TB patients. Comparable methods, led to the identification of HLA-E-restricted Mtb epitopes recognized by CD8(+) T-cells. A genome-wide unbiased antigen discovery approach was applied to analyze the in vivo Mtb gene expression profiles in the lungs of mice, resulting in the identification of IVE-TB antigens, which are expressed during infection in the lung, the main target organ of Mtb. IVE-TB antigens induce strong T-cell responses in long-term latently Mtb infected individuals, and represent an interesting new group of TB antigens for vaccination. In summary, new tools have helped expand our view on the Mtb antigenome involved in human cellular immunity and provided new candidates for TB vaccination.
鉴于仅探索了一小部分 Mtb 表达组抗原来鉴定能够激活人类 T 细胞反应的抗原，这对于设计更好的结核病疫苗接种策略至关重要，因此应更加重视创新方法来发现新的 Mtb 抗原并探索其在感染的几个阶段的功能。也迫切需要更好的 TB 疫苗保护性抗原，鉴于 MVA85 疫苗的结果令人失望，该疫苗未能在 BCG 接种婴儿中诱导额外的保护作用（1）。此外，针对相关抗原的免疫反应可能有助于鉴定 TB 特异性生物标志物特征。在这里，我们描述了揭示此类 Mtb 抗原的新工具和策略的效力。使用针对不同 Mtb 感染阶段的蛋白质，发现了许多潜伏相关的 Mtb DosR 调控子以及与复苏相关的促进因子蛋白的新抗原，这些抗原被 CD4(+)和 CD8(+) T 细胞识别。此外，通过采用 MHC 结合算法和生物信息学，结合高通量人类 T 细胞筛选和四聚体，在结核病患者中鉴定出 HLA-Ia 限制的多能性 CD8(+) T 细胞。类似的方法导致鉴定出 HLA-E 限制的 Mtb 表位，被 CD8(+) T 细胞识别。应用全基因组无偏见的抗原发现方法来分析小鼠肺部中的体内 Mtb 基因表达谱，导致鉴定出 IVE-TB 抗原，该抗原在肺部感染期间表达，是 Mtb 的主要靶器官。IVE-TB 抗原在长期潜伏性 Mtb 感染个体中诱导强烈的 T 细胞反应，是结核病疫苗接种的一个有趣的新抗原组。总之，新工具帮助我们扩大了对涉及人类细胞免疫的 Mtb 抗原组的认识，并为结核病疫苗接种提供了新的候选物。
