TCF-1和LEF-1协同调控滤泡辅助T细胞的后期分化和记忆维持的分子机制研究

Follicular helper T cells (TFH cells), a unique subset of CD4 helper T cells, are specialized to facilitate the establishment of a GC reaction and the selection of GC B cells bearing high-affinity antigen receptors for final differentiation into memory B cells and long-lived plasma cells. Applicant previous work demonstrated TCF-1, a downstream transcription factor of canonical Wnt pathway, functions as an important hub upstream of the Bcl-6–Blimp1 axis to initiate and secure the differentiation of TFH cells during acute viral infection. However, it resulted in similar frequency and number of fully-differentiated TFH cells when TCF-1 was ablated in late-differentiation of TFH cells, but significant decrease when LEF-1, another downstream transcription factor of canonical Wnt pathway, was ablated together. Moreover, it caused that the memory TFH cells were progressively lost over time and recall response of memory TFH cells was decreased when TCF-1 was ablated in memory TFH cells. Considering the compensation from LEF-1, double knockout mice of TCF-1 and LEF-1 driven by ERT2Cre have been choosen to study the mechanisms of TCF-1 and LEF-1 in regulating the late-differentiation and memory-maintenance of TFH cells. This research will shed new light on providing novel strategies and targets against the design of vaccine and adjuvant and the diseases caused by dysregulation of TFH cells.

滤泡辅助T细胞(TFH)是帮助B细胞应答产生抗体的关键辅助T细胞亚群。申请人的前期工作报道了经典Wnt通路下游转录因子TCF-1通过调控Bcl-6-Blimp1轴从而启动TFH细胞早期分化的分子机制。但申请人进一步研究发现，在TFH细胞的后期分化中诱导敲除TCF-1后，完全分化的TFH细胞没有明显变化；而同时敲除经典Wnt通路下游另一转录因子LEF-1后，完全分化的TFH细胞却显著减少。另一方面，在记忆TFH细胞中诱导敲除TCF-1后，记忆TFH细胞的维持和再次应答能力都有一定程度的降低。因此，考虑到LEF-1的代偿作用，申请人拟以ERT2Cre介导的TCF-1和LEF-1双条件诱导敲除小鼠模型为对象，通过LCMV感染来研究TCF-1和LEF-1协同调控TFH细胞的后期分化和记忆维持的分子机制。本项目的研究成果将为疫苗和佐剂的设计以及治疗TFH细胞失调引起的各种疾病提供新思路和新靶点。

T细胞在控制病毒、胞内细菌感染以及肿瘤发生发展中具有决定性的作用。本项目围绕着T细胞的发育、分化以及功能进行了一系列的研究：1) 发现并阐述了转录因子LXRβ通过调控IL-7Rα的表达从而促进SP胸腺细胞的存活的分子机制，并已发表在免疫学1区期刊《Cellular & Molecular Immunology》上；2) 发现并阐述了转录因子Bcl6在病毒急性感染过程中影响记忆性CD8 T细胞形成的分子机制，并已发表在免疫学2区SCI期刊《Journal of Immunology》上；3) 发现并阐述了铈纳米颗粒促进CTL细胞的杀伤功能的分子机制，并已发表在SCI期刊《Biomaterials Science》上；4) 分析了在疟疾感染模型中，转录因子TCF-1在各种T细胞亚群中的表达情况，并已发表在国内核心期刊《免疫学杂志》上；5) 已证实在CD4 T细胞中双条件敲除转录因子TCF-1和LEF-1并不能影响Tfh细胞的分化，而只影响了Tfh细胞的功能，相关数据正在整理中。

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