我校西南医院卞修武院士团队在Science发表研究成果——Tfh细胞通过分泌SOSTDC1促进Tfr细胞分化
发布人:zhangyilin 发布时间:3/17/2021 4:14:40 PM  浏览次数:4127次
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Tfh细胞通过分泌SOSTDC1促进Tfr细胞分化

吴鑫 刘新东 卞修武 王岩

 

新近研究显示,伴随着生发中心反应,一类由胸腺来源的nTreg细胞分化形成滤泡调节性T细胞(follicular regulatory T cell, Tfr)能够负向调控体液免疫的中心轴“滤泡辅助性T细胞(follicular helper T cell, Tfh)–B细胞–抗体”。Tfr细胞不仅可以维持正常体液免疫应答,还能防止抗体介导的自身免疫性疾病发生。然而,nTreg如何分化成Tfr细胞在领域内尚不清楚。

研究者首先明确SOSTDC1在Tfh细胞中表达,发现~30% Tfh细胞特异性高表达SOSTDC1,并形成特定的细胞亚型SOSTDC1+ Tfh。SOSTDC1主要在T-B细胞边界区域的Tfh细胞和成纤维网状基质细胞(FRCs)中表达。进一步采用单细胞转录组测序分析发现SOSTDC1+ Tfh新亚型是由SOSTDC1Tfh细胞分化生成。

随后,考察SOSTDC1+ Tfh细胞的功能。SOSTDC1+ Tfh细胞与经典的Tfh细胞功能不同,它不能帮助B细胞产生抗体。在Sostdc1–/–小鼠的流感病毒感染模型以及KLH特异性抗原免疫模型中,发现敲除SOSTDC1能增强生发中心反应:伴随着生发中心B细胞数目的增多, Tfr细胞数目明显减少。进一步采用骨髓移植构建嵌合体小鼠,发现Tfh细胞来源的SOSTDC1能够促进Tfr细胞分化。

进一步探究SOSTDC1促进Tfr细胞分化的分子机制,研究者通过转录组分析发现,SOSTDC1Tfh细胞表达大量的WNT配体基因,而SOSTDC1+ Tfh细胞表达拮抗WNT信号的基因。通过对SOSTDC1敲除情况下的Tfr细胞分析,发现受损Tfr细胞呈现炎性细胞特征:大量表达IL-4、IL-5和IL-6等炎性细胞因子,同时Tfr细胞表现为WNT/β-catenin信号通路过度激活,表明Tfh可通过SOSTDC1促进Tfr细胞的分化和功能。

上述研究结果由陆军军医大学第一附属医院刘新东、卞修武和王岩教授所带领的团队在Science杂志2020年8月21日在线发表了题为SOSTDC1-producing follicular helper T cells promote regulatory follicular T cell differentiation的论著。该研究率先发现Tfh细胞的新亚群并定义为SOSTDC1+ Tfh细胞,阐明其通过促进Tfr细胞分化,负反馈调控抗体产生。这一发现不仅为疫苗研发策略提供了理论依据,还为自身免疫性疾病的药物研发、提高抗病毒感染策略提供新视角。

 

附:英文摘要

SOSTDC1-producing follicular helper T cells promote regulatory follicular T cell differentiation

Xin Wu1, Yun Wang1, Rui Huang1, Qujing Gai1, Haofei Liu1, Meimei Shi1, Xiang Zhang1, Yonglin Zuo1, Longjuan Chen1, Qiwen Zhao1, Yu Shi1, Fengchao Wang2, Xiaowei Yan3, Huiping Lu4, Senlin Xu1, Xiaohong Yao1, Lin Chen2, Xia Zhang1, Qiang Tian3,6†, Ziyan Yang5, Bo Zhong7, Chen Dong4, Yan Wang1*, Xiu-wu Bian1*, and Xindong Liu1*

Affiliations:

1 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P. R. China.

2 State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing 400038, P. R. China.

3 Institute for Systems Biology, Seattle, WA 98103, USA.

4 Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, P. R. China.

5 Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, P. R. China.

6 National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

7 Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, P. R. China.

*Correspondence to: xindongliu@hotmail.com, bianxiuwu@263.net or wang_yan1977@hotmail.com

† Current address, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, P. R. China.

Abstract:

Germinal center (GC) responses potentiate the generation of follicular regulatory T (Tfr) cells. However, the molecular cues driving Tfr cell formation remain unknown. Here, we show that sclerostin domain-containing protein 1 (SOSTDC1), secreted by a subpopulation of follicular helper T (Tfh) cells and T–B cell border-enriched fibroblastic reticular cells (FRCs), is developmentally required for Tfr cell generation. Fate tracking and transcriptome assessment in reporter mice establishes SOSTDC1-expressing Tfh cells as a unique T cell population that develops after SOSTDC1 Tfh cells and loses the ability to help B cells for antibody production. Notably, Sostdc1 ablation in Tfh cells results in substantially reduced Tfr cell numbers and consequently elevated GC responses. Mechanistically, SOSTDC1 blocks the WNT–β-catenin axis and facilitates Tfr cell differentiation.

 


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