Walker Naomi F, Opondo Charles, Meintjes Graeme, Jhilmeet Nishtha, Friedland Jon S, Elkington Paul T, Wilkinson Robert J, Wilkinson Katalin A
Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa.
Infectious Diseases and Immunity, and Imperial College Wellcome Trust Centre for Global Health, Imperial College London, United Kingdom.
Clin Infect Dis. 2020 Apr 15;70(9):1865-1874. doi: 10.1093/cid/ciz501.
Tuberculosis (TB) is the leading cause of mortality and morbidity in people living with human immunodeficiency virus (HIV) infection (PLWH). PLWH with TB disease are at risk of the paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) when they commence antiretroviral therapy. However, the pathophysiology is incompletely understood and specific therapy is lacking. We investigated the hypothesis that invariant natural killer T (iNKT) cells contribute to innate immune dysfunction associated with TB-IRIS.
In a cross-sectional study of 101 PLWH and HIV-uninfected South African patients with active TB and controls, iNKT cells were enumerated using α-galactosylceramide-loaded CD1d tetramers and subsequently functionally characterized by flow cytometry. In a second study of 49 people with HIV type 1 (HIV-1) and active TB commencing antiretroviral therapy, iNKT cells in TB-IRIS patients and non-IRIS controls were compared longitudinally.
Circulating iNKT cells were reduced in HIV-1 infection, most significantly the CD4+ subset, which was inversely associated with HIV-1 viral load. iNKT cells in HIV-associated TB had increased surface CD107a expression, indicating cytotoxic degranulation. Relatively increased iNKT cell frequency in patients with HIV-1 infection and active TB was associated with development of TB-IRIS following antiretroviral therapy initiation. iNKT cells in TB-IRIS were CD4+CD8- subset depleted and degranulated around the time of TB-IRIS onset.
Reduced iNKT cell CD4+ subsets as a result of HIV-1 infection may skew iNKT cell functionality toward cytotoxicity. Increased CD4- cytotoxic iNKT cells may contribute to immunopathology in TB-IRIS.
结核病（TB）是人类免疫缺陷病毒（HIV）感染者（PLWH）死亡和发病的主要原因。患有结核病的PLWH在开始抗逆转录病毒治疗时，有发生矛盾的结核相关免疫重建炎症综合征（TB-IRIS）的风险。然而，其病理生理学尚未完全了解，且缺乏特异性治疗方法。我们研究了不变自然杀伤T（iNKT）细胞促成与TB-IRIS相关的先天性免疫功能障碍这一假说。
在一项对101例PLWH以及未感染HIV的南非活动性结核病患者和对照进行的横断面研究中，使用负载α-半乳糖神经酰胺的CD1d四聚体对iNKT细胞进行计数，随后通过流式细胞术对其功能进行表征。在第二项针对49例1型HIV（HIV-1）感染者和开始抗逆转录病毒治疗的活动性结核病患者的研究中，对TB-IRIS患者和非IRIS对照中的iNKT细胞进行了纵向比较。
HIV-1感染会使循环中的iNKT细胞减少，最显著的是CD4+亚群，其与HIV-1病毒载量呈负相关。HIV相关结核病中的iNKT细胞表面CD107a表达增加，表明存在细胞毒性脱颗粒。HIV-1感染且患有活动性结核病患者中相对增加的iNKT细胞频率与抗逆转录病毒治疗开始后TB-IRIS的发生有关。TB-IRIS中的iNKT细胞在TB-IRIS发病时CD4+CD8-亚群减少且发生脱颗粒。
HIV-1感染导致iNKT细胞CD4+亚群减少，可能会使iNKT细胞功能偏向细胞毒性。CD4-细胞毒性iNKT细胞增加可能会导致TB-IRIS中的免疫病理改变。
