Egr2在T细胞调控生发中心反应和体液免疫应答中的作用

Germinal center (GC) reaction is the most important physiological process in humoral immune response, which is positively or negatively regulated by Follicular helper T cells (TFH) or Follicular regulatory T cells (TFR). However, the mechanism underlying regulation of differentiation and function of these two subsets is not well defined. We have previously found that deletion of gene encoding transcription factor Egr2 specifically in T cells results in defect of germinal center reactions in response to viral infection, including reduction of TFH cells, GC B cells as well as plasma cells. Further analysis revealed that Egr2 is not cell-intrinsically required for the differentiation of TFH cells. First, we will investigate whether Egr2 has direct impact on B cell help of TFH cells. Then we will explore whether deficiency of Egr2 enhances differemtiation, stability or function of Treg cells, especially TFR cells. Finally, by using RNA-seq and Chip-seq, we will identify the target genes of Egr2 and then elucidate the molecular mechanism underlying the regulation of germinal center reaction by Egr2. The completion of this project might shed light on regulation of humoral immune response by TFH cells or TFR cells, and may be useful in both therapeutic intervention in human infectious diseases or autoimmunity diseases and rational vaccine design.

生发中心反应是体液免疫应答中最重要的生理过程，分别受到滤泡辅助性T细胞(TFH)和滤泡调节性T细胞(TFR)的正或负的调节，但是调控这两类细胞分化和功能的机制目前并不是很清楚。我们的前期研究发现，转录因子Egr2基因在T细胞特异性的缺失导致针对病毒感染的生发中心反应的阻断，包括TFH细胞、生发中心B细胞和浆细胞的减少。进一步研究表明，Egr2对TFH细胞的分化并不是必需的。首先，我们将进一步分析Egr2是否直接影响TFH细胞的功能；其次，我们将研究Egr2的缺失是否增强了Treg特别是TFR细胞分化、稳定性或功能；最后，我们将利用组学方法，去鉴定Egr2的靶基因，以阐明Egr2调控生发中心反应的分子作用机制。上述研究的完成有望进一步完善TFH/TFR细胞调控体液免疫反应的作用机制，为传染性疾病和自身免疫疾病的治疗、以及疫苗的研制优化提供理论基础。

本项目原定目标为探讨转录因子Egr2在滤泡辅助性T细胞(TFH)和滤泡调节性T细胞(TFR)的分化及功能中的作用，但是在项目获批不久，类似的结果就已经被英国Ping Wang实验室报道出来了。因此，我们被迫改变了研究计划。我们发现T细胞表达的转录因子Zeb1是T细胞介导的细胞免疫和T细胞依赖性的B细胞及抗体反应所必需的。 Zeb1并不直接参与T细胞活化、增殖的调控，而是阻止T细胞走向凋亡。Zeb1的缺失导致T细胞表达大量的E-cadherin （Cdh1）及其它细胞连接相关分子，但是E-cadherin的高表达并不是T细胞容易发生凋亡的原因。同时我们发现一些免疫抑制分子，例如：AhR, CD73（Nt5e）等，在Zeb1缺失的T细胞中也高度表达。通过共培养实验，我们发现Zeb1缺失的T细胞中高表达的芳香烃受体(AhR)感受抗原呈递细胞中吲哚胺2,3-二氧化酶(IDO)催化的色氨酸代谢产物，增强了T细胞的凋亡信号通路。本项目的成果将为靶向Ido-Kyn-AhR通路的抑制剂在感染性疾病和自身免疫疾病的治疗、肿瘤免疫治疗上的应用带来新的希望。