慢性感染诱导具有细胞毒性功能的CD4+T细胞(CD4CTLs);目前,目前尚不清楚潜伏性结核(LTB)和活动性结核(ATB)是否诱导CD4CTL。来自四个患者组的血浆和细胞-未感染接触(UC),LTB,和ATB(分为敏感[DS-TB]-或耐药[DR-TB]-药物)-通过流式细胞术进行评估,q-PCR,和蛋白质组学。数据显示ATB患者的CD4+T细胞频率增加,CD8+T细胞频率降低。后者显示以CD39、CD279和TIM-3表达为特征的耗尽样特征。ATB有高频率的CD4+穿孔素+细胞,提示CD4CTL谱。颗粒酶A的表达(在转录水平),颗粒酶B,颗粒溶素,和穿孔素,以及基因T-bet(Tbx21)和NKG2D(Klrk1),在富集的CD4+T细胞中,证实了ATB期间CD4+T细胞的细胞毒性特征(DS-TB比DR-TB更强)。此外,蛋白质组学分析显示HSP70(在DS-TB中)和膜联蛋白A5(在DR-TB中)的存在,它们是与有利于CD4CTL谱相关的分子。最后,我们发现结核分枝杆菌的脂质增加了DR-TB患者中CD4CTL的存在.我们的数据表明,ATB的特征是耗尽样CD8+T细胞,which,以及特定的微环境,有利于CD4CTL的存在。
Chronic infections induce CD4+ T-cells with cytotoxic functions (CD4 CTLs); at present, it is still unknown whether latent tuberculosis (LTB) and active tuberculosis (ATB) induce CD4 CTLs. Plasma and cells from four patient groups-uninfected contact (UC), LTB, and ATB (divided as sensitive [DS-TB]- or resistant [DR-TB]-drug)-were evaluated by flow cytometry, q-PCR, and proteomics. The data showed that ATB patients had an increased frequency of CD4+ T-cells and a decreased frequency of CD8+ T-cells. The latter displays an exhausted-like profile characterized by CD39, CD279, and TIM-3 expression. ATB had a high frequency of CD4 + perforin+ cells, suggesting a CD4 CTL profile. The expression (at the transcriptional level) of granzyme A, granzyme B, granulysin, and perforin, as well as the genes T-bet (Tbx21) and NKG2D (Klrk1), in enriched CD4+ T-cells, confirmed the cytotoxic signature of CD4+ T-cells during ATB (which was stronger in DS-TB than in DR-TB). Moreover, proteomic analysis revealed the presence of HSP70 (in DS-TB) and annexin A5 (in DR-TB), which are molecules that have been associated with favoring the CD4 CTL profile. Finally, we found that lipids from Mycobacterium tuberculosis increased the presence of CD4 CTLs in DR-TB patients. Our data suggest that ATB is characterized by exhausted-like CD8+ T-cells, which, together with a specific microenvironment, favor the presence of CD4 CTLs.