First Department of Medicine, Section Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
German Center for Infection Research (DZIF), Partner Site Hamburg Lübeck Borstel Riems, Hamburg, Germany.
Front Immunol. 2022 Apr 22;13:867167. doi: 10.3389/fimmu.2022.867167. eCollection 2022.
γδ T cells are unconventional T cells that have been demonstrated to be crucial for the pathogenesis and potentially for the cure of HIV-1 infection. The ectonucleotidase CD39 is part of the purinergic pathway that regulates immune responses by degradation of pro-inflammatory ATP in concert with CD73. Few studies on the expression of the ectoenzymes CD73 and CD39 on human γδ T cells in HIV have been performed to date.
PBMC of n=86 HIV-1-infected patients were compared to PBMC of n=26 healthy individuals using 16-color flow cytometry determining the surface expression of CD39 and CD73 on Vδ1 and Vδ2 T cells in association with differentiation (CD45RA, CD28, CD27), activation and exhaustion (TIGIT, PD-1, CD38, and HLA-DR), and assessing the intracellular production of pro- and anti-inflammatory cytokines (IL-2, TGF-ß, TNF-α, Granzyme B, IL-10, IFN-γ) after stimulation with PMA/ionomycin.
CD39 and CD73 expression on γδ T cells were inversed in HIV infection which correlated with HIV disease progression and immune activation. CD39, but not CD73 expression on γδ T cells of ART-treated patients returned to levels comparable with those of healthy individuals. Only a small subset (<1%) of γδ T cells co-expressed CD39 and CD73 in healthy or HIV-infected individuals. There were significantly more exhausted and terminally differentiated CD39+ Vδ1 T cells regardless of the disease status. Functionally, IL-10 was only detectable in CD39+ γδ T cells after stimulation in all groups studied. Viremic HIV-infected patients showed the highest levels of IL-10 production. The highest percentage of IL-10+ cells was found in the small CD39/CD73 co-expressing γδ T-cell population, both in healthy and HIV-infected individuals. Also, CD39+ Vδ2 T cells produced IL-10 more frequently than their CD39+ Vδ1 counterparts in all individuals regardless of the HIV status.
Our results point towards a potential immunomodulatory role of CD39+ and CD73+ γδ T cells in the pathogenesis of chronic HIV infection that needs further investigation.
γδ T 细胞是一种非常规 T 细胞，已被证明对 HIV-1 感染的发病机制和潜在治疗至关重要。细胞外核苷酸酶 CD39 是嘌呤能途径的一部分，通过与 CD73 一起降解促炎 ATP 来调节免疫反应。迄今为止，针对 HIV 中人类 γδ T 细胞上的外切酶 CD73 和 CD39 的表达进行了很少的研究。
使用 16 色流式细胞术比较了 n=86 例 HIV-1 感染患者和 n=26 例健康个体的 PBMC，确定了 Vδ1 和 Vδ2 T 细胞表面 CD39 和 CD73 的表达与分化（CD45RA、CD28、CD27）、激活和衰竭（TIGIT、PD-1、CD38 和 HLA-DR）相关，并评估了刺激后前炎症细胞因子（IL-2、TGF-β、TNF-α、颗粒酶 B、IL-10、IFN-γ）的细胞内产生。
HIV 感染中 CD39 和 CD73 在 γδ T 细胞上的表达呈相反趋势，与 HIV 疾病进展和免疫激活相关。经 ART 治疗的患者的 CD39 和 CD73 在 γδ T 细胞上的表达恢复到与健康个体相当的水平。在健康或 HIV 感染个体中，只有一小部分（<1%）γδ T 细胞共表达 CD39 和 CD73。无论疾病状态如何，耗尽和终末分化的 CD39+Vδ1 T 细胞都明显更多。功能上，在所有研究组中，刺激后仅在 CD39+γδ T 细胞中可检测到 IL-10。病毒血症 HIV 感染患者显示出最高水平的 IL-10 产生。在健康和 HIV 感染个体中，均在小的 CD39/CD73 共表达 γδ T 细胞群体中发现 IL-10+细胞的百分比最高。此外，在所有个体中，无论 HIV 状态如何，CD39+Vδ2 T 细胞比其 CD39+Vδ1 对应物更频繁地产生 IL-10。
我们的结果表明 CD39+和 CD73+γδ T 细胞在慢性 HIV 感染的发病机制中可能具有潜在的免疫调节作用，需要进一步研究。
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