Bhatnagar Nupur, Girard Pierre-Marie, Lopez-Gonzalez Moises, Didier Céline, Collias Lio, Jung Corinne, Bollens Diane, Duvivier Claudine, Von Platen Cassandre, Scott-Algara Daniel, Weiss Laurence
Institut Pasteur, Unité Cytokines et Inflammation, Paris, France.
AP-HP, Hôpital Saint-Antoine, Paris, France.
Front Immunol. 2017 Sep 25;8:1189. doi: 10.3389/fimmu.2017.01189. eCollection 2017.
Although conventional regulatory T cells (Tregs) are sufficient in controlling low residual T-cell activation in ART-treated patients, they are not efficient in controlling exaggerated immune activation associated with high levels of HIV replication in primary HIV infection (PHI). Our previous data suggested that double negative (DN) T cells including mainly γδ DN T cells play a role in the control of immune activation in PHI. Since γδ T cells are capable of exerting regulatory functions, we investigated their implication as Tregs in PHI as well as chronic HIV infection (CHI). In a cross-sectional study of 58 HIV-infected patients, in the primary and the chronic phase either ART-treated or untreated (UT), we analyzed phenotype and cytokine production of γδ T cells using flow cytometry. Cytokine production was assessed following stimulation with isopentenyl pyrophosphate or plate-bound anti-CD3/anti-CD28 monoclonal antibodies. We found that the proportion of γδ T cells negatively correlated with CD8 T-cell activation in PHI patients. Furthermore, we found that in these patients, the Vδ2 receptor bearing (Vδ2) γδ T cells were strongly activated, exhibited low terminal differentiation, and produced the anti-inflammatory cytokine, TGF-β. In contrast, in UT-CHI, we observed a remarkable expansion of γδ T cells, where the Vδ2 γδ T cells comprised of an elevated proportion of terminally differentiated cells producing high levels of IFN-γ but very low levels of TGF-β. We also found that this loss of regulatory feature of γδ T cells in CHI was a lasting impairment as we did not find recovery of TGF-β production even in ART-CHI patients successfully treated for more than 5 years. Our data therefore suggest that during the primary HIV infection, Vδ2 γδ T cells may act as Tregs controlling immune activation through production of TGF-β. However, in CHI, γδ T cells transform from an anti-inflammatory into pro-inflammatory cytokine profile and participate in sustenance of immune activation.
尽管传统调节性T细胞（Tregs）足以控制接受抗逆转录病毒治疗（ART）患者中残留的低水平T细胞激活，但它们在控制原发性HIV感染（PHI）中与高水平HIV复制相关的过度免疫激活方面效率不高。我们之前的数据表明，主要包括γδ双阴性（DN）T细胞的DN T细胞在控制PHI中的免疫激活中发挥作用。由于γδ T细胞能够发挥调节功能，我们研究了它们作为Tregs在PHI以及慢性HIV感染（CHI）中的作用。在一项对58名HIV感染患者的横断面研究中，这些患者处于原发性和慢性期，无论是否接受ART治疗，我们使用流式细胞术分析了γδ T细胞的表型和细胞因子产生情况。在用异戊烯基焦磷酸或板结合抗CD3/抗CD28单克隆抗体刺激后评估细胞因子产生情况。我们发现，在PHI患者中，γδ T细胞的比例与CD8 T细胞激活呈负相关。此外，我们发现，在这些患者中，携带Vδ2受体（Vδ2）的γδ T细胞被强烈激活，表现出低终末分化，并产生抗炎细胞因子转化生长因子-β（TGF-β）。相比之下，在未接受治疗的CHI患者中，我们观察到γδ T细胞显著扩增，其中Vδ2 γδ T细胞中终末分化细胞的比例升高，产生高水平的干扰素-γ（IFN-γ）但TGF-β水平极低。我们还发现，CHI中γδ T细胞这种调节特性的丧失是一种持续性损伤，因为即使在成功接受ART治疗超过5年的CHI患者中，我们也未发现TGF-β产生的恢复。因此，我们的数据表明，在原发性HIV感染期间，Vδ2 γδ T细胞可能作为Tregs通过产生TGF-β来控制免疫激活。然而，在CHI中，γδ T细胞从抗炎细胞因子谱转变为促炎细胞因子谱，并参与维持免疫激活。
