Corss-talk of signals between immunoreceptors and cytokine receptors for development of allergy

包括肥大细胞和NKT细胞在内的多种免疫细胞与过敏性疾病有关。这些细胞表达与免疫球蛋白 E (IgE) 或各种抗原发生反应的免疫受体，并被受体与其各自配体相互作用所传递的信号激活。此外，这些细胞产生的细胞因子会恶化过敏性炎症。 MIST 是 SLP-76 家族衔接蛋白的成员，参与免疫受体信号转导，在多种骨髓和淋巴来源的细胞因子依赖性造血细胞系中表达。我们在本研究中通过分析 MIST 基因的转录调控元件证明 STAT5 参与肥大细胞中细胞因子介导的 MIST 基因表达上调。此外，我们通过使用 MIST 缺陷小鼠发现，MIST 作为高亲和力 IgE 受体介导的肥大细胞脱颗粒和细胞因子产生的正调节因子。 TCR 介导的 NKT 细胞产生 IFN-γ 和 IL-4 也受到 MIST 的正向调节。相比之下，MIST 似乎充当 NK 细胞受体介导的 IFN-γ 产生的负调节因子。 MIST 的这种功能转换是通过 MIST 与 Fgr 的相互作用来调节的，Fgr 是一种在 NK 细胞中表达的 Src 家族激酶，但在 NKT 细胞中不表达，表明 MIST 是控制不同细胞群中不同反应的重要分子开关。总而言之，MIST 作为免疫受体和细胞因子信号传导之间的纽带，可以增强免疫受体介导的过敏反应部位免疫细胞的激活，其中积累了丰富的细胞因子。因此，抑制 MIST 表达和/或功能可能是抗过敏治疗的潜在目标，因为 MIST 缺陷降低了受体介导的肥大细胞和 NKT 细胞激活的阈值。

Various immune cells including mast cells and NKT cells are involved in allergic diseases. These cells express immunoreceptors that react with immunoglobulin E(IgE) or various antigens, and are activated by signals delivered by the interaction of receptors with their respective ligands. In adddition, cytokines produced by these cells deteriorate allergic inflammation. MIST is a member of SLP-76 family adaptor proteins that are involved in immunoreceptor signal transduction, and is expressed in a variety of cytokine-dependent hematopoietic cell lines of myeloid and lymphoid origin. We have demonstrated in the present study that STAT5 is involved in cytokine-mediated up-regulation of MIST gene expression in mast cells by analyzing transcription regulatory elements of the MIST gene. Furthermore, we have revealed that MIST functions as a positive regulator for high-affinity IgE receptor-mediated mast cell degranulation and cytokine production by using MIST-deficient mice. TCR-mediated IFN-γ and IL-4 production by NKT cells was also positively regulated by MIST. In contrast, MIST appears to act as a negative regulator for NK cell receptor-mediated IFN-γ production. This functional conversion of MIST was regulated by the interaction of MIST with Fgr, an Src family kinase expressed in NK cells but not in NKT cells, indicating MIST as an important molecular switch to control diverse responses in different cell populations. Taken together, MIST serves as a link between immunoreceptor- and cytokine-signaling, and can enhance immunoreceptor-mediated activation of immune cells at the site of allergic reactions where abundant cytokines are accumulated. Thus, suppression of MIST expression and/or function could be a potential target for anti-allergic therapy, since MIST deficiency lower the threshold for receptor-mediated activation of mast cells and NKT cells.