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Wanli Liu's lab revealed a novel mechanism of B cell receptor co-receptor FcRL1 to enhance B cell activation and function

On July 17, 2019, Wanli Liu’s lab from Institute of Immunology Tsinghua University published a research article entitled “Fc receptor–like 1 intrinsically recruits c-Abl to enhance B cell activation and function” in Science Advances. This paper reported a novel molecular mechanism of FcRL1 as a BCR co-stimulatory molecule for B-cell activation and function.

The intensity of B cell immune activation is directly related to the differentiation fate of subsequent B lymphocytes and the efficiency of humoral immune response, so B cell activation needs to be precisely regulated. In past studies, CD19 has been considered to be the most classical activated B cell receptor (BCR) co-receptor during B cell activation, and is involved in the upregulation of BCR activation signals and subsequent cell proliferation and differentiation regulation. In this study, we investigated the signaling mechanism of Fc receptor-like 1 (FcRL1), a newly identified BCR co-receptor, in B cell activation and antibody production. We found that FcRL1 was passively recruited into B cell immunological synapses upon BCR engagement in the absence of FcRL1 crosslinking, suggesting a new model in which FcRL1 intrinsically regulated B cell activation and function. Indeed, BCR crosslinking alone led to the phosphorylation of tyrosine residue in the intracellular Y281ENV motif of FcRL1, which provided a docking site for c-Abl, an SH2 domain-containing kinase. The FcRL1 and c-Abl signaling module, in turn, augmented B cell activation and proliferation. FcRL1-deficient mice exhibited significantly impaired formation of extrafollicular plasmablasts and germinal centers, along with decreased antibody production upon either T cell-dependent or T cell-independent antigen stimulation. In marked contrast, B cell development is not affected in FcRL1-deficient mice. These results revealed a ligand-independent BCR signal-enhancing function of FcRL1 through its recruitment to B cell immunological synapse and the subsequent recruitment of c-Abl, which is distinct from that of the well-studied BCR activating co-receptor CD19.

Dr. Wanli Liu’s lab has been focusing on basic immunology research of B lymphocyte, integrating an interdisciplinary platform to investigate regulatory mechanisms of B cell activation and pathogenesis of related immune diseases. After the establishment of his own lab in 2012, Dr. Liu has made some achievements in pathogenesis study of B cell related autoimmune diseases (Science, 2018; J Exp Med. 2016; Leukemia 2019&2019; Cell Research 2018; J Immunol, 2014&2017); mechanical force sensitivity and threshold for the activation of BCR (J Cell Biol, 2018; Science Signaling, 2018; eLife, 2015&2017; Eur J Immunol, 2015; J Immunol, 2013); B cell activation regulation through lipid metabolism network (Cell, 2018; Science Immunology, 2017; Cell Reports, 2017; Nature Communications, 2015); B cell activation regulation through BCR complex (Science Advances, 2019; PNAS, 2016; Chemical Science, 2016; J Leukoc Biol, 2015).

The study is funded by the National Science Foundation of China, the Ministry of Science and Technology of People's Republic of China. Xingwang Zhao and Meng Zhao, two PhD students from School of Life Sciences, and Hengyi Xie a master student from School of Life Sciences, Tsinghua University, are the co-first authors.

Wanli Liu from School of Life Sciences, Tsinghua University, Tae Jin Kim from School of Medicine, Sungkyunkwan University, and Quan-Zhen Li from Department of Immunology and Microarray Core Facility, University of Texas Southwestern Medical Center, are the co- corresponding author of this article.

(Fc receptor-like 1 intrinsically recruits c-Abl to enhance B cell activation and function)

Online linkhttps://advances.sciencemag.org/content/5/7/eaaw0315

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