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Wanli Liu's lab reported a mechanism of mechanical regulation of B lymphocyte activation in eLife

  Wanli Liu’s lab reported a mechanism of mechanical regulation of B lymphocyte activation in eLife

 

On July 31, 2017, a research team led by Prof Wanli Liu from school of Life sciences, Institute for Immunology of Tsinghua University (IITU), Tsinghua University published a research article entitled “Substrate stiffness governs the initiation of B cell activation by the concerted signaling of PKCβ and focal adhesion kinase”. In this study, the group reported the molecular mechanism by which the B lymphocyte immune activation is precisely regulated by its mechanosensing capability. The results showed that protein kinase Cβ (PKCβ) and focal adhesion kinase co-regulate the activation of B lymphocyte on the antigen presenting substrates of different stiffness. Samina Shaheen (from Pakistan), an international PhD student from school of Life sciences Tsinghua University, Zhengpeng Wan, a PhD student from PTN (Peking University, Tsinghua University and the Beijing Institute of Life Sciences joint training  program), and undergraduate student Zongyu Li from school of life sciences are the co-first authors of this article. Dr. Wanli Liu is the corresponding author of this article.

This study required a strong integration of molecular biology, cell biology, biochemistry, new materials science, high-resolution live cell imaging and biophysics and other disciplines of cross-advantages. It involves genetically modified mice spleen B cells and autoimmune disease patient’s blood B cells and other experimental materials widely used in the research, and it has got strong supports from both domestic and international scientific groups.

B lymphocytes, as an important participant in the process of antibody immune response maintaining human health, is activated by recognition of the pathogen through the membrane bound surface receptor called B-cell receptor (BCR). The previous work of this group revealed that B lymphocytes have the mechanical sensing capability, through which BCRs accurately identify the physical and chemical properties of the antigen. In this research, the molecular mechanism of B lymphocyte immune activation was studied systematically by combining the antigen presenting substrates system with different rigidity and the high speed high resolution imaging system based on total internal reflection and confocal fluorescence microscopy. The paper reported that the mechanosensing-governed activation of B cell requires BCR signaling molecules. PMA-induced activation of PKCβ can bypass the Btk and PLC-g2 signaling molecules that are usually required for B cells to discriminate substrate stiffness. Instead, PKCβ-dependent activation of FAK is required, leading to FAK-mediated potentiation of B cell spreading and adhesion responses. FAK inactivation or deficiency impaired B cell discrimination of substrate stiffness. Conversely, adhesion molecules greatly enhanced this capability of B cells. Lastly, B cells derived from rheumatoid arthritis (RA) patients exhibited an altered BCR response to substrate stiffness in comparison to healthy controls. These results provide a molecular explanation for how the initiation of B cell activation discriminates substrate stiffness through a PKCβ-mediated FAK activation dependent manner. These studies provide new insights into immune recognition, activation and regulation for B lymphocytes, helping people understand autoimmune diseases and providing important information on the pathogenesis of related diseases, which can lead to the better development of the vaccine on the basis of strong theoretical knowledge.

Dr. Wanli Liu’s group has been committed to the use of combining immunological and biochemical experimental approaches with cutting-edge high resolution high speed live cell and molecule imaging techniques and biophysics research methods to investigate the function of lymphocyte cells. Following the publication in the Journal of Immunology in 2013 and the publication in the European Journal of Immunology and eLife in 2015 about immunological activation of B lymphocytes by mechanical force, this achievement is his new contribution to this field. The study is funded by the National Science Foundation of China, the Ministry of Science and Technology of People's Republic of China. Samina Shaheen is supported by the Chinese government scholarship program.

 

Figure: Substrate stiffness governs the initiation of B cell activation by the concerted activation of PKCβ and focal adhesion kinase

 

 

Link of the paper: https://elifesciences.org/articles/23060

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