Laboratory of Integrative Immunology, National Institute of Respiratory Diseases Ismael Cosío Villegas, Calzada de Tlalpan 4502, Tlalpan, 14080 Mexico City, Mexico.
PECEM Graduate Program, Faculty of Medicine, National Autonomous University of Mexico, Circuito Escolar, Ciudad Universitaria, Coyoacán, 04510 Mexico City, Mexico.
J Leukoc Biol. 2024 Sep 2;116(3):440-455. doi: 10.1093/jleuko/qiae060.
Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after T cell receptor (TCR)-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular nicotinamide adenine dinucleotide and nicotinamide mononucleotide concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the oxygen consumption rate/extracellular acidification rate ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ecto-CD38 catalytic activity in TM cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous proinflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morphofunctionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.
尽管有大量证据表明 T 细胞 CD38 表达与 HIV 感染发病机制相关，但它作为 CD4T 细胞免疫代谢调节剂的作用尚不清楚。我们发现，CD38 的细胞外糖基水解酶活性限制了 Jurkat T CD4 细胞中 T 细胞受体 (TCR) 刺激后的代谢重编程，同时还降低了细胞内烟酰胺腺嘌呤二核苷酸和烟酰胺单核苷酸的浓度。选择性消除 CD38 的外酶功能使它们能够在 TCR 信号转导时降低耗氧率/细胞外酸化率比值，并增加细胞循环、增殖、存活和 CD40L 诱导。在慢性 HIV 感染患者的 TM 细胞中，抑制外切-CD38 的催化活性可恢复 TCR 触发的反应，包括分化和效应功能，同时使异常增加的基础糖酵解、细胞循环和自发性促炎细胞因子产生正常化。此外，外切酶 CD38 的阻断还可使 HIV+患者和健康个体的细胞中基础和 TCR 诱导的线粒体形态和功能正常化，同时增加呼吸能力。TCR 相关刺激中外切酶 CD38 的免疫代谢限制与 CD4T 细胞生物学以及 HIV 疾病中外切酶 CD38 过表达的有害影响有关。
