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.