Loss of IP3 Receptor–Mediated Ca2+ Release in Mouse B Cells Results in Abnormal B Cell Development and Function

Abstract Intracellular calcium (Ca2+) mobilization after engagement of the BCR has been proposed to play an important role in B cell development and function. BCR activation causes an initial Ca2+ release from the endoplasmic reticulum that is mediated by inositol 1,4,5-trisphosphate receptor (IP3R) and then triggers store-operated Ca2+ entry once endoplasmic reticulum Ca2+ store is depleted. Store-operated Ca2+ entry has been shown to regulate B cell function but is dispensable for B cell development. By contrast, the function of IP3R-mediated Ca2+ release in B cells remains to be determined. In this study, we generated a B cell–specific IP3R triple-knockout (IP3R-TKO) mouse model and revealed that loss of IP3Rs increased transitional B cell numbers and reduced recirculating mature B cell numbers in bone marrow. In the peripheral tissues, the numbers of conventional B2 B cells and B1 B cells were both significantly decreased in IP3R-TKO mice. Ablation of IP3Rs also dramatically reduced BCR-mediated B cell proliferation and survival. Furthermore, T cell–dependent and T cell–independent Ab responses were altered in IP3R-TKO mice. In addition, deletion of IP3Rs reduced IL-10–producing regulatory B cell numbers and led to defects in NFAT activation, which together resulted in decreased IL-10 secretion. Taken together, our study demonstrated for the first time, to our knowledge, that IP3R-mediated Ca2+ release plays an essential role in regulating B cell development, proliferation, Ab production, and B cell regulatory function in vivo.