The Calcium Sensors STIM1 and STIM2 Control B Cell Regulatory Function through Interleukin-10 Production

SummaryA chief Ca2+ entry pathway in immune cells is store-operated Ca2+ (SOC) influx, which is triggered by depletion of Ca2+ from the endoplasmic reticulum (ER). However, its physiological role in B cells remains elusive. Here, we show that ER calcium sensors STIM1- and STIM2-induced SOC influx is critical for B cell regulatory function. B cell-specific deletion of STIM1 and STIM2 in mice caused a profound defect in B cell receptor (BCR)-induced SOC influx and proliferation. However, B cell development and antibody responses were unaffected. Remarkably, B cells lacking both STIM proteins failed to produce the anti-inflammatory cytokine IL-10 because of defective activation of nuclear factor of activated T cells (NFAT) after BCR stimulation. This resulted in exacerbation of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our data establish STIM-dependent SOC influx as a key signal for B cell regulatory function required to limit autoimmunity.

Graphical AbstractFigure optionsDownload high-quality image (307 K)Download as PowerPoint slideHighlights
► STIM proteins are required for BCR-mediated SOC influx and proliferation
► STIM proteins are dispensable for B cell development and antibody responses
► STIM-mediated NFAT activation induces IL-10 production by B cells
► STIM-dependent IL-10 production by B cells suppresses the development of autoimmunity