Laboratory of AIDS and Molecular Immunology, Oswaldo Cruz Institute (FIOCRUZ), Rio de Janeiro, Brazil.
Clinical Research Laboratory on Mycobacteria, National Institute of Infectious Diseases Evandro Chagas (FIOCRUZ), Rio de Janeiro, Brazil.
Front Immunol. 2019 Aug 13;10:1800. doi: 10.3389/fimmu.2019.01800. eCollection 2019.
Tuberculosis (TB) is the most common comorbidity and the leading cause of death among HIV-infected individuals. Although the combined antiretroviral therapy (cART) during TB treatment improves the survival of TB/HIV patients, the occurrence of immune reconstitution inflammatory syndrome (IRIS) in some patients poses clinical and scientific challenges. This work aimed to evaluate blood innate lymphocytes during therapeutic intervention for both diseases and their implications for the onset of IRIS. Natural killer (NK) cells, invariant NKT cells (iNKT), γδ T cell subsets, and NK functional activity were characterized by multiparametric flow cytometry in the following groups: 33 TB/HIV patients (four with paradoxical IRIS), 27 TB and 25 HIV mono-infected subjects (prior to initiation of TB treatment and/or cART and during clinical follow-up to 24 weeks), and 25 healthy controls (HC). Concerning the NK cell repertoire, several activation and inhibitory receptors were skewed in the TB/HIV patients compared to those in the other groups, especially the HCs. Significantly higher expression of CD158a ( = 0.025), NKp80 ( = 0.033), and NKG2C ( = 0.0076) receptors was detected in the TB/HIV IRIS patients than in the non-IRIS patients. Although more NK degranulation was observed in the TB/HIV patients than in the other groups, the therapeutic intervention did not alter the frequency during follow-up (weeks 2-24). A higher frequency of the γδ T cell population was observed in the TB/HIV patients with inversion of the Vδ2/Vδ2 ratio, especially for those presenting pulmonary TB, suggesting an expansion of particular γδ T subsets during TB/HIV co-infection. In conclusion, HIV infection impacts the frequency of circulating NK cells and γδ T cell subsets in TB/HIV patients. Important modifications of the NK cell repertoire were observed after anti-TB treatment (week 2) but not during the cART/TB follow-up (weeks 6-24). An increase of CD161 NK cells was related to an unfavorable outcome. Despite the low number of cases, a more preserved NK cell profile was detected in IRIS patients previous to treatment, suggesting a role for these cells in IRIS onset. Longitudinal evaluation of the NK repertoire showed the impact of TB treatment and implicated these cells in TB pathogenesis in TB/HIV co-infected patients.
结核病（TB）是 HIV 感染者最常见的合并症和主要死因。尽管在结核病治疗期间联合抗逆转录病毒治疗（cART）提高了结核病/艾滋病患者的生存率，但一些患者发生免疫重建炎症综合征（IRIS）给临床和科研带来了挑战。本研究旨在评估两种疾病治疗干预期间的血液固有淋巴细胞及其对 IRIS 发生的影响。通过多参数流式细胞术，在以下组别中对自然杀伤（NK）细胞、不变自然杀伤 T 细胞（iNKT）、γδ T 细胞亚群和 NK 功能活性进行了特征分析：33 例结核病/艾滋病患者（其中 4 例为矛盾性 IRIS）、27 例结核病和 25 例艾滋病单感染患者（在开始结核病治疗和/或 cART 之前以及临床随访至 24 周时）和 25 名健康对照者（HC）。关于 NK 细胞库，与其他组相比，TB/HIV 患者的多种激活和抑制受体发生倾斜，尤其是 HC。在 TB/HIV IRIS 患者中，检测到 CD158a（=0.025）、NKp80（=0.033）和 NKG2C（=0.0076）受体的表达明显高于非 IRIS 患者。虽然 TB/HIV 患者的 NK 脱颗粒作用较其他组更为明显，但在随访期间（第 2-24 周），治疗干预并未改变其频率。在 TB/HIV 患者中观察到γδ T 细胞群的频率较高，Vδ2/Vδ2 比值发生反转，特别是那些患有肺结核的患者，表明在 TB/HIV 合并感染期间，特定的γδ T 亚群发生扩张。总之，HIV 感染影响 TB/HIV 患者循环 NK 细胞和γδ T 细胞亚群的频率。在抗结核治疗后（第 2 周）观察到 NK 细胞库的重要改变，但在 cART/结核病随访期间（第 6-24 周）没有改变。CD161 NK 细胞的增加与不良结局相关。尽管病例数较少，但在治疗前的 IRIS 患者中检测到保存较好的 NK 细胞表型，提示这些细胞在 IRIS 发病机制中起作用。NK 库的纵向评估显示了结核病治疗的影响，并暗示这些细胞在 TB/HIV 合并感染患者的结核病发病机制中起作用。
