Pivotal role of STIM2, but not STIM1, in IL-4 production by IL-3–stimulated murine basophils

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Science Signaling  09 Apr 2019:
Vol. 12, Issue 576, eaav2060
DOI: 10.1126/scisignal.aav2060

STIMulating basophils

The ER-resident Ca2+ sensors stromal interaction molecule 1 (STIM1) and STIM2 promote store-operated Ca2+ entry, which is required for immune cell function (see the Focus by Alansary and Niemeyer). Using basophils from conditional knockout mice, Yoshikawa et al. found that STIM2 was required for production of the cytokine IL-4 in vitro in response to IL-3, whereas STIM1 was necessary for IL-4 production in response to antigen-antibody complexes. In mice, the development of antigen-dependent allergic inflammation required STIM1 expression in basophils, but the response to a combination of IL-3 and IL-33 required basophil expression of STIM2. These results suggest that the STIM proteins in basophils have distinct roles in mediating responses to antigens or cytokines.


Basophils have nonredundant roles in various immune responses that require Ca2+ influx. Here, we examined the role of two Ca2+ sensors, stromal interaction molecule 1 and 2 (STIM1 and STIM2), in basophil activation. We found that loss of STIM1, but not STIM2, impaired basophil IL-4 production after stimulation with immunoglobulin E (IgE)–containing immune complexes. In contrast, when basophils were stimulated with IL-3, loss of STIM2, but not STIM1, reduced basophil IL-4 production. This difference in STIM proteins was associated with distinct time courses of Ca2+ influx and transcription of the Il4 gene that were elicited by each stimulus. Similarly, basophil-specific STIM1 expression was required for IgE-driven chronic allergic inflammation in vivo, whereas STIM2 was required for IL-4 production after combined IL-3 and IL-33 treatment in mice. These data indicate that STIM1 and STIM2 have differential roles in the production of IL-4, which are stimulus dependent. Furthermore, these results illustrate the vital role of STIM2 in basophils, which is often considered to be less important than STIM1.

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