Larson Erica C, Ellis Amy L, Rodgers Mark A, Gubernat Abigail K, Gleim Janelle L, Moriarty Ryan V, Balgeman Alexis J, de Menezes Yonne T, Ameel Cassaundra L, Fillmore Daniel J, Pergalske Skyler M, Juno Jennifer A, Maiello Pauline, Chishti Harris B, Lin Philana Ling, Godfrey Dale I, Kent Stephen J, Pellicci Daniel G, Ndhlovu Lishomwa C, O'Connor Shelby L, Scanga Charles A
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Infect Immun. 2024 Dec 10;92(12):e0031324. doi: 10.1128/iai.00313-24. Epub 2024 Oct 30.
Children living with HIV have a higher risk of developing tuberculosis (TB), a disease caused by the bacterium (Mtb). Gamma delta (γδ) T cells in the context of HIV/Mtb coinfection have been understudied in children despite evidence suggesting γδ T cells assist with Mtb control. We investigated whether boosting a specific subset of γδ T cells, phosphoantigen-reactive Vγ9+Vδ2+ cells, could improve TB outcome using a nonhuman primate model of pediatric HIV/Mtb coinfection. Juvenile Mauritian cynomolgus macaques (MCM), equivalent to 4- to 8-year-old children, were infected intravenously (i.v.) with SIV. After 6 months, MCM were coinfected with a low dose of Mtb and then randomized to receive zoledronate (ZOL), a drug that increases phosphoantigen levels, ( = 5; i.v.) at 3 and 17 days after Mtb accompanied by recombinant human IL-2 (s.c.) for 5 days following each ZOL injection. A similarly coinfected MCM group ( = 5) was injected with saline as a control. Vγ9+Vδ2+ γδ T cell frequencies spiked in the blood, but not airways, of ZOL+IL-2-treated MCM following the first dose, however, were refractory to the second dose. At necropsy 8 weeks after Mtb, ZOL+IL-2 treatment did not reduce pathology or bacterial burden. γδ T cell subset frequencies in granulomas did not differ between treatment groups. These data show that transiently boosting peripheral γδ T cells with ZOL+IL-2 soon after Mtb coinfection of SIV-infected MCM did not improve Mtb host defense.
感染艾滋病毒的儿童患结核病（TB）的风险更高，结核病是由结核分枝杆菌（Mtb）引起的一种疾病。尽管有证据表明γδT细胞有助于控制结核分枝杆菌，但在艾滋病毒/结核分枝杆菌合并感染的情况下，儿童中的γδT细胞一直未得到充分研究。我们使用儿童艾滋病毒/结核分枝杆菌合并感染的非人灵长类动物模型，研究增强γδT细胞的一个特定亚群，即磷酸抗原反应性Vγ9+Vδ2+细胞，是否能改善结核病的转归。相当于4至8岁儿童的幼年毛里求斯食蟹猴（MCM）通过静脉注射（i.v.）感染了猴免疫缺陷病毒（SIV）。6个月后，MCM被低剂量的结核分枝杆菌合并感染，然后随机分为两组，一组在结核分枝杆菌感染后第3天和第17天接受唑来膦酸（ZOL）（n = 5；静脉注射），ZOL是一种能提高磷酸抗原水平的药物，每次ZOL注射后皮下注射重组人白细胞介素-2（s.c.），持续5天。另一个同样合并感染的MCM组（n = 5）注射生理盐水作为对照。在第一次注射后，ZOL+IL-2治疗的MCM血液中Vγ9+Vδ2+γδT细胞频率飙升，但气道中未出现这种情况，然而，第二次注射后则无反应。在结核分枝杆菌感染8周后进行尸检时，ZOL+IL-2治疗并未减轻病理变化或细菌负荷。各治疗组肉芽肿中的γδT细胞亚群频率没有差异。这些数据表明，在SIV感染的MCM合并感染结核分枝杆菌后不久，用ZOL+IL-2短暂增强外周γδT细胞并不能改善结核分枝杆菌的宿主防御。
