Simonson Andrew W, Zeppa Joseph J, Bucsan Allison N, Chao Michael C, Pokkali Supriya, Hopkins Forrest, Chase Michael R, Vickers Andrew J, Sutton Matthew S, Winchell Caylin G, Myers Amy J, Ameel Cassaundra L, Kelly Ryan, Krouse Ben, Hood Luke E, Li Jiaxiang, Lehman Chelsea C, Kamath Megha, Tomko Jaime, Rodgers Mark A, Donlan Rachel, Chishti Harris, Jacob Borish H, Klein Edwin, Scanga Charles A, Fortune Sarah, Lin Philana Ling, Maiello Pauline, Roederer Mario, Darrah Patricia A, Seder Robert A, Flynn JoAnne L
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine; Pittsburgh, PA, USA.
Center for Vaccine Research, University of Pittsburgh School of Medicine; Pittsburgh, PA, USA.
bioRxiv. 2024 May 17:2024.05.14.594183. doi: 10.1101/2024.05.14.594183.
Tuberculosis (TB) is a major cause of morbidity and mortality worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the route and dose of BCG vaccination from 5×10 CFU ID to 5×10 CFU intravenous (IV) resulted in prevention of infection and disease in a rigorous, highly susceptible non-human primate model of TB. Identifying the immune mechanisms of protection for IV BCG will facilitate development of more effective vaccines against TB. Here, we depleted select lymphocyte subsets in IV BCG vaccinated macaques prior to Mtb challenge to determine the cell types necessary for that protection. Depletion of CD4 T cells or all CD8α expressing lymphoycytes (both innate and adaptive) resulted in loss of protection in most macaques, concomitant with increased bacterial burdens (~4-5 log thoracic CFU) and dissemination of infection. In contrast, depletion of only adaptive CD8αβ+ T cells did not significantly reduce protection against disease. Our results demonstrate that CD4 T cells and innate CD8α+ lymphocytes are critical for IV BCG-induced protection, supporting investigation of how eliciting these cells and their functions can improve future TB vaccines.
尽管新生儿普遍接种皮内（ID）卡介苗，但结核病（TB）仍是全球发病和死亡的主要原因。我们之前证明，将卡介苗接种的途径和剂量从5×10 CFU皮内接种改为5×10 CFU静脉内（IV）接种，可在严格的、高度易感的结核病非人灵长类动物模型中预防感染和疾病。确定静脉内卡介苗的免疫保护机制将有助于开发更有效的抗结核疫苗。在此，我们在结核分枝杆菌攻击之前，对静脉内接种卡介苗的猕猴体内特定淋巴细胞亚群进行耗竭，以确定这种保护所需的细胞类型。耗竭CD4 T细胞或所有表达CD8α的淋巴细胞（先天和适应性）导致大多数猕猴失去保护，同时细菌负荷增加（约4-5个对数级的胸腔CFU）并出现感染播散。相比之下，仅耗竭适应性CD8αβ+ T细胞并没有显著降低对疾病的保护作用。我们的结果表明，CD4 T细胞和先天CD8α+淋巴细胞对静脉内卡介苗诱导的保护至关重要，这支持了对如何激发这些细胞及其功能以改进未来抗结核疫苗的研究。
