Chancellor Andrew, White Andrew, Tocheva Anna S, Fenn Joe R, Dennis Mike, Tezera Liku, Singhania Akul, Elliott Tim, Tebruegge Marc, Elkington Paul, Gadola Stephan, Sharpe Sally, Mansour Salah
Academic Unit of Clinical and Experimental Sciences, University of Southampton, Faculty of Medicine and University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
Public Health England, National Infections Service, Porton Down, Salisbury, United Kingdom.
Tuberculosis (Edinb). 2017 Jul;105:86-95. doi: 10.1016/j.tube.2017.04.011. Epub 2017 Apr 28.
Correlates of immune protection that reliably predict vaccine efficacy against Mycobacterium tuberculosis (Mtb) infection are urgently needed. Invariant NKT cells (iNKTs) are CD1d-dependent innate T cells that augment host antimicrobial immunity through production of cytokines, including interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We determined peripheral blood iNKT numbers, their proliferative responses and iNKT subset proportions after in vitro antigen expansion by α-galactosylceramide (αGC) in a large cohort of mycobacteria-naïve non-human primates, and macaques from Bacillus Calmette-Guerin (BCG) vaccine and Mtb challenge studies. Animals studied included four genetically distinct groups of macaques within cynomolgus and rhesus species that differ in their susceptibility to Mtb infection. We demonstrate significant differences in ex vivo iNKT frequency between groups, which trends towards an association with susceptibility to Mtb, but no significant difference in overall iNKT proliferative responses. Susceptible animals exhibited a skewed CD4/CD8 iNKT subset ratio in comparison to more Mtb-resistant groups. Correlation of iNKT subsets post BCG vaccination with clinical disease manifestations following Mtb challenge in the Chinese cynomolgus and Indian rhesus macaques identified a consistent trend linking increased CD8 iNKTs with favourable disease outcome. Finally, a similar iNKT profile was conferred by BCG vaccination in rhesus macaques. Our study provides the first detailed characterisation of iNKT cells in macaque tuberculosis infection, suggesting that iNKT repertoire differences may impact on disease outcome, which warrants further investigation.
迫切需要能够可靠预测抗结核分枝杆菌（Mtb）感染疫苗效力的免疫保护相关因素。不变自然杀伤T细胞（iNKT细胞）是依赖CD1d的先天性T细胞，可通过产生包括干扰素（IFN）-γ和肿瘤坏死因子（TNF）-α在内的细胞因子来增强宿主抗菌免疫力。我们测定了一大群未接触过分枝杆菌的非人灵长类动物以及来自卡介苗（BCG）疫苗接种和Mtb攻击研究的猕猴外周血中iNKT细胞数量、它们的增殖反应以及体外经α-半乳糖神经酰胺（αGC）抗原扩增后的iNKT亚群比例。所研究的动物包括食蟹猴和恒河猴这两个物种内四个遗传上不同的猕猴组，它们对Mtb感染的易感性不同。我们证明了各组之间体外iNKT频率存在显著差异，这一差异有与Mtb易感性相关的趋势，但总体iNKT增殖反应没有显著差异。与对Mtb更具抗性的组相比，易感动物的CD4/CD8 iNKT亚群比例存在偏差。在中国食蟹猴和印度恒河猴中，卡介苗接种后iNKT亚群与Mtb攻击后的临床疾病表现之间的相关性确定了一个一致的趋势，即CD8 iNKT细胞增加与良好的疾病结局相关。最后，恒河猴经卡介苗接种后呈现出类似的iNKT特征。我们的研究首次详细描述了猕猴结核感染中iNKT细胞的特征，表明iNKT细胞库差异可能影响疾病结局，这值得进一步研究。
