Jogdand Gajendra M, Mohanty Suchitra, Devadas Satish
T Cell and Immune Response, Infectious Disease Biology, Institute of Life Sciences , Bhubaneswar , India.
Tumor Virology Lab, Infectious Disease Biology, Institute of Life Sciences , Bhubaneswar , India.
Front Immunol. 2016 Nov 23;7:520. doi: 10.3389/fimmu.2016.00520. eCollection 2016.
The follicular helper T (Tfh) cells help is critical for activation of B cells, antibody class switching, and germinal center (GC) formation. The Tfh cells are characterized by the expression of CXC chemokine receptor 5 (CXCR5), ICOS, programed death 1 (PD-1), B cell lymphoma 6 (BCL-6), and IL-21. They are involved in clearing infections and are adversely linked with autoimmune diseases and also have a role in viral replication as well as clearance. On the one hand, Tfh cells are generated from naive CD4 T cells with sequential steps involving cytokine signaling (IL-21, IL-6, IL-12, activin A), migration, and positioning in the GC by CXCR5, surface receptors (ICOS/ICOSL, signaling lymphocyte activation molecule-associated protein/signaling lymphocyte activation molecule) as well as transcription factor (BCL-6, c-Maf, and signal transducer and activator of transcription 3) signaling and repressor miR155. On the other hand, Tfh generation is negatively regulated at specific steps of Tfh generation by specific cytokine (IL-2, IL-7), surface receptor (PD-1, CTLA-4), transcription factors B lymphocyte maturation protein 1, signal transducer and activator of transcription 5, T-bet, KLF-2 signaling, and repressor miR 146a. Interestingly, miR-17-92 and FOXO1 act as a positive as well as a negative regulator of Tfh differentiation depending on the time of expression and disease specificity. Tfh cells are also generated from the conversion of other effector T cells as exemplified by Th1 cells converting into Tfh during viral infection. The mechanistic details of effector T cells conversion into Tfh are yet to be clear. To manipulate Tfh cells for therapeutic implication and or for effective vaccination strategies, it is important to know positive and negative regulators of Tfh generation. Hence, in this review, we have highlighted and interlinked molecular signaling from cytokines, surface receptors, transcription factors, ubiquitin ligase, and microRNA as positive and negative regulators for Tfh differentiation.
滤泡辅助性T（Tfh）细胞的辅助作用对于B细胞的激活、抗体类别转换以及生发中心（GC）的形成至关重要。Tfh细胞的特征在于表达CXC趋化因子受体5（CXCR5）、诱导共刺激分子（ICOS）、程序性死亡蛋白1（PD-1）、B细胞淋巴瘤6（BCL-6）和白细胞介素21（IL-21）。它们参与清除感染，与自身免疫性疾病存在负相关，并且在病毒复制及清除过程中也发挥作用。一方面，Tfh细胞由初始CD4 T细胞产生，其过程包括细胞因子信号传导（IL-21、IL-6、IL-12、激活素A）、迁移以及通过CXCR5、表面受体（ICOS/ICOS配体、信号淋巴细胞激活分子相关蛋白/信号淋巴细胞激活分子）以及转录因子（BCL-6、c-Maf和信号转导及转录激活因子3）信号传导和抑制性微小RNA155（miR155）在生发中心定位。另一方面，在Tfh细胞产生的特定步骤中，Tfh细胞的生成受到特定细胞因子（IL-2、IL-7）、表面受体（PD-1、细胞毒性T淋巴细胞相关蛋白4）、转录因子B淋巴细胞成熟蛋白1、信号转导及转录激活因子5、T盒转录因子、Krüppel样因子2信号传导以及抑制性微小RNA146a（miR 146a）的负调控。有趣的是，根据表达时间和疾病特异性，微小RNA17-92和叉头框蛋白O1（FOXO1）既作为Tfh分化的正调控因子，也作为负调控因子。Tfh细胞也可由其他效应性T细胞转化而来，例如在病毒感染期间Th1细胞转化为Tfh细胞。效应性T细胞转化为Tfh细胞的机制细节尚不清楚。为了将Tfh细胞用于治疗目的和/或有效的疫苗接种策略，了解Tfh细胞生成的正调控因子和负调控因子非常重要。因此，在本综述中，我们着重介绍并相互关联了来自细胞因子、表面受体、转录因子、泛素连接酶和微小RNA的分子信号传导，将其作为Tfh分化的正调控因子和负调控因子。
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