Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Central Laboratory for Advanced Diagnostics and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy.
Eur J Immunol. 2018 Feb;48(2):293-305. doi: 10.1002/eji.201747184. Epub 2017 Dec 15.
HLA-E presented antigens are interesting targets for vaccination given HLA-Es' essentially monomorphic nature. We have shown previously that Mycobacterium tuberculosis (Mtb) peptides are presented by HLA-E to CD8 effector T cells, but the precise phenotype and functional capacity of these cells remains poorly characterized. We have developed and utilized in this study a new protocol combining HLA-E tetramer with intracellular staining for cytokines, transcription factors and cytotoxic molecules to characterize these cells in depth. We confirm in this study the significantly increased ex vivo frequency of Mtb-peptide/HLA-E-TM CD8 T cells in the circulation of patients with active tuberculosis (TB). HLA-E restricted CD8 T cells from TB patients produced more IL-13 than cells from controls or subjects with latent tuberculosis infection (LTBI). Compared to total CD8 T cells, HLA-E restricted cells produced more IFNγ, IL-4, IL-10, and granulysin but less granzyme-A. Moreover, compared to "classical" Mtb specific HLA-A2 restricted CD8 T cells, HLA-E restricted CD8 T cells produced less TNFα and perforin, but more IL-4. In conclusion, HLA-E restricted- Mtb specific cells can produce Th2 cytokines directly.
HLA-E 呈递的抗原是疫苗接种的有趣靶点，因为 HLA-E 本质上是单态的。我们之前已经表明，结核分枝杆菌（Mtb）肽通过 HLA-E 呈递给 CD8 效应 T 细胞，但这些细胞的确切表型和功能能力仍未得到很好的描述。我们在这项研究中开发并利用了一种新的方案，将 HLA-E 四聚体与细胞内细胞因子、转录因子和细胞毒性分子染色相结合，深入研究这些细胞。我们在这项研究中证实，与潜伏性结核感染（LTBI）或对照者相比，活动性结核病（TB）患者循环中 Mtb 肽/HLA-E-TM CD8 T 细胞的体外频率显著增加。与对照者或 LTBI 患者相比，来自 TB 患者的 HLA-E 限制性 CD8 T 细胞产生更多的 IL-13。与总 CD8 T 细胞相比，HLA-E 限制性细胞产生更多的 IFNγ、IL-4、IL-10 和颗粒酶，但更少的颗粒酶-A。此外，与“经典”Mtb 特异性 HLA-A2 限制性 CD8 T 细胞相比，HLA-E 限制性 CD8 T 细胞产生更少的 TNFα 和穿孔素，但更多的 IL-4。总之，HLA-E 限制性 Mtb 特异性细胞可以直接产生 Th2 细胞因子。
