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Published on: April 20, 2021
STIM-mediated calcium influx regulates maintenance and selection of germinal center B cells
Yutaro Yada1,2, Masanori Matsumoto3,4, Takeshi Inoue3
1Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Insights
Stromal interacting molecule (STIM) proteins are crucial for germinal center B cell survival. STIM deficiency enhances apoptosis by impairing Bcl2a1 upregulation, impacting B cell selection during immune responses.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Germinal center (GC) B cell selection relies on B cell receptor (BCR) signaling for high-affinity antibody production.
- Store-operated calcium (Ca2+) entry, mediated by STIM1 and STIM2, is a key BCR-triggered signaling pathway.
- The precise role of STIM proteins in GC B cell function remains largely undefined.
Purpose of the Study:
- To investigate the role of STIM1 and STIM2 in BCR signaling and GC B cell selection.
- To determine the impact of STIM deficiency on GC B cell competitiveness, survival, and proliferation.
Main Methods:
- Generation of B cell-specific STIM-deficient mice.
- Analysis of GC formation, B cell populations, proliferation, apoptosis, and antigen presentation.
- Assessment of Bcl2a1 expression and NFAT activation following BCR stimulation.
Main Results:
- STIM-deficient B cells exhibited reduced competitiveness within the GC response.
- Loss of STIM proteins led to decreased high-affinity B cells in late GC formation.
- STIM deficiency enhanced B cell apoptosis by impairing Bcl2a1 upregulation, independent of proliferation or antigen presentation.
- STIM-mediated NFAT activation was essential for BCR-induced Bcl2a1 expression.
Conclusions:
- STIM proteins are critical regulators of GC B cell survival through the NFAT-Bcl2a1 pathway.
- STIM-mediated calcium signaling supports optimal selection and maintenance of high-affinity GC B cells post-antigen capture.
Abstract:
Positive selection of high-affinity germinal center (GC) B cells is driven by antigen internalization through their B cell receptor (BCR) and presentation to follicular helper T cells. However, the requirements of BCR signaling in GC B cells remain poorly understood. Store-operated Ca2+ entry, mediated by stromal interacting molecule 1 (STIM1) and STIM2, is the main Ca2+ influx pathway triggered by BCR engagement. Here, we showed that STIM-deficient B cells have reduced B cell competitiveness compared with wild-type B cells during GC responses. B cell-specific deletion of STIM proteins decreased the number of high-affinity B cells in the late phase of GC formation. STIM deficiency did not affect GC B cell proliferation and antigen presentation but led to the enhancement of apoptosis due to the impaired upregulation of anti-apoptotic Bcl2a1. STIM-mediated activation of NFAT was required for the expression of Bcl2a1 after BCR stimulation. These findings suggest that STIM-mediated survival signals after antigen capture regulate the optimal selection and maintenance of GC B cells.
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