Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses. Using mass cytometry (CyTOF) to analyze the immune cell composition in the lamina propria (LP) of patients with ulcerative colitis (UC) and Crohn's disease (CD), we observed an enrichment of CD4⁺ effector T cells producing IL-17A and TNF, CD8⁺ T cells producing IFNγ, T regulatory (Treg) cells, and innate lymphoid cells (ILC). The function of these immune cells is regulated by store-operated Ca²⁺ entry (SOCE), which results from the opening of Ca²⁺ release-activated Ca²⁺ (CRAC) channels formed by ORAI and STIM proteins. We observed that the pharmacologic inhibition of SOCE attenuated the production of proinflammatory cytokines including IL-2, IL-4, IL-6, IL-17A, TNF, and IFNγ by human colonic T cells and ILCs, reduced the production of IL-6 by B cells and the production of IFNγ by myeloid cells, but had no effect on the viability, differentiation, and function of intestinal epithelial cells. T cell-specific deletion of CRAC channel genes in mice showed that Orai1, Stim1, and Stim2-deficient T cells have quantitatively distinct defects in SOCE, which correlate with gradually more pronounced impairment of cytokine production by Th1 and Th17 cells and the severity of IBD. Moreover, the pharmacologic inhibition of SOCE with a selective CRAC channel inhibitor attenuated IBD severity and colitogenic T cell function in mice. Our data indicate that SOCE inhibition may be a suitable new approach for the treatment of IBD.

中文翻译：

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储存操作的钙进入控制炎症性肠病中的先天和适应性免疫细胞功能

炎症性肠病 (IBD) 的特点是肠道免疫反应失调。使用质谱流式细胞术 (CyTOF) 分析溃疡性结肠炎 (UC) 和克罗恩病 (CD) 患者固有层 (LP) 中的免疫细胞组成，我们观察到产生 IL-17A 和 TNF 的 CD4 ⁺效应 T 细胞富集、CD8 ⁺ T 细胞产生 IFNγ、T 调节 (Treg) 细胞和先天淋巴细胞 (ILC)。这些免疫细胞的功能受储存操作的 Ca ²⁺进入 (SOCE) 的调节，SOCE 是由 Ca ²⁺释放激活的 Ca ^{2+开放引起的。}(CRAC) 通道由 ORAI 和 STIM 蛋白形成。我们观察到 SOCE 的药理学抑制作用减弱了人结肠 T 细胞和 ILC 产生的促炎细胞因子，包括 IL-2、IL-4、IL-6、IL-17A、TNF 和 IFNγ，减少了 IL-6 的产生。 B 细胞和骨髓细胞产生 IFNγ，但对肠上皮细胞的活力、分化和功能没有影响。小鼠 CRAC 通道基因的 T 细胞特异性缺失表明Orai1、Stim1和Stim2- 缺陷 T 细胞在 SOCE 中具有数量上明显的缺陷，这与 Th1 和 Th17 细胞产生的细胞因子产生逐渐更明显的损害以及 IBD 的严重程度相关。此外，选择性 CRAC 通道抑制剂对 SOCE 的药理抑制作用可减轻小鼠的 IBD 严重程度和致结肠 T 细胞功能。我们的数据表明，SOCE 抑制可能是治疗 IBD 的一种合适的新方法。