Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University, Philadelphia, 19102, PA, USA.
Genentech, San Francisco, 94080, CA, USA.
Nat Commun. 2019 Feb 18;10(1):823. doi: 10.1038/s41467-019-08801-1.
Follicular helper T cells (Tfh) play critical roles instructing, and initiating T-cell dependent antibody responses. The underlying mechanisms that enhance their function is therefore critical for vaccine development. Here we apply gene array analysis identifying adenosine deaminase (ADA) as a key molecule that delineates a human Tfh helper program in proliferating circulating Tfh (cTfh) cells and Germinal Centers Tfh (GC-Tfh). ADA-1 expression and enzymatic activity are increased in efficient cTfh2-17/GC-Tfh cells. Exogenous ADA-1 enhances less efficient cTfh1 and pro-follicular Tfh PD-1+ CXCR5+ cells to provide B cell help, while pharmacological inhibition of ADA-1 activity impedes cTfh2-17/GC-Tfh function and diminished antibody response. Mechanistically, ADA-1 controls the Tfh program by influencing IL6/IL-2 production, controlling CD26 extracellular expression and could balance signals through adenosine receptors. Interestingly, dysfunctional Tfh from HIV infected-individual fail to regulate the ADA pathway. Thus, ADA-1 regulates human Tfh and represents a potential target for development of vaccine strategy.
滤泡辅助 T 细胞（Tfh）在指导和启动 T 细胞依赖的抗体反应中发挥关键作用。因此，增强其功能的潜在机制对于疫苗的开发至关重要。在这里，我们应用基因阵列分析确定腺苷脱氨酶（ADA）作为一种关键分子，它可以区分增殖的循环滤泡辅助 T 细胞（cTfh）和生发中心滤泡辅助 T 细胞（GC-Tfh）中的人类 Tfh 辅助程序。在有效的 cTfh2-17/GC-Tfh 细胞中，ADA-1 的表达和酶活性增加。外源性 ADA-1 增强效率较低的 cTfh1 和前滤泡 Tfh PD-1+CXCR5+细胞提供 B 细胞帮助，而 ADA-1 活性的药理学抑制会阻碍 cTfh2-17/GC-Tfh 功能并减少抗体反应。从机制上讲，ADA-1 通过影响 IL6/IL-2 的产生来控制 Tfh 程序，控制 CD26 的细胞外表达，并通过腺苷受体平衡信号。有趣的是，来自 HIV 感染个体的功能失调的 Tfh 不能调节 ADA 途径。因此，ADA-1 调节人类 Tfh，并代表了开发疫苗策略的潜在目标。
