by Osaka University

Credit: Journal of Experimental Medicine (2023). DOI: 10.1084/jem.20222178

Germinal centers (GCs) are specialized microenvironments where antigen (Ag)-specific B cells undergo antibody affinity maturation and clonal expansion. Positive selection of high-affinity GC B cells is driven by Ag internalization through their B cell receptor (BCR) and presentation to follicular helper T (Tfh) 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.

Researchers Yutaro Yada, Masanori Matsumoto, Tomohiro Kurosaki, Yoshihiro Baba, and their research group from Osaka University have now shown that STIM-deficient B cells have reduced B cell competitiveness compared to 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.

The research is published in the Journal of Experimental Medicine.

STIM deficiency did not affect GC B cell proliferation and Ag 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 Ag capture regulate the optimal selection and maintenance of GC B cells.

GCs are composed of a dark zone where B cells undergo clonal expansion and somatic hypermutation in the immunoglobulin gene and a light zone where B cells capture Ags on follicular dendritic cells (FDCs) and present these to Tfh cells.

In the light zone, high-affinity GC B cells receive a survival signal through induction of the anti-apoptotic bcl2a1 gene, which is required for NFAT activation by STIM-mediated Ca²⁺ influx upon Ag stimulation. Thus, the B cell survival after Ag recognition in GCs may promote affinity maturation by increasing the probability of receiving Tfh cell assistance.

More information: Yutaro Yada et al, STIM-mediated calcium influx regulates maintenance and selection of germinal center B cells, Journal of Experimental Medicine (2023). DOI: 10.1084/jem.20222178

Provided by Osaka University