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

包括肥大细胞和NKT细胞在内的各种免疫细胞参与了变态反应性疾病。这些细胞表达免疫受体，与免疫球蛋白E(IgE)或各种抗原反应，并由受体与各自的配体相互作用传递的信号激活。此外，这些细胞产生的细胞因子会加重过敏性炎症。MIST是SLP-76家族的一员，参与免疫受体信号转导，表达于多种髓系和淋巴系细胞因子依赖的造血细胞系中。本研究通过对MIST基因转录调控元件的分析，证明STAT5参与了细胞因子介导的肥大细胞MIST基因表达的上调。此外，我们还发现，在高亲和力的IgE受体介导的肥大细胞脱颗粒和细胞因子的产生方面，MIST在MIST缺陷小鼠中发挥着积极的调节作用。MIST对TcR介导的干扰素-γ和IL-4的产生也有正向调节作用。相反，MIST似乎对NK细胞受体介导的干扰素-γ的产生起到负调节作用。MIST的这种功能转换受MIST与FGR相互作用的调节，FGR是一种在NK细胞中表达而在NKT细胞中不表达的Src家族激酶，表明MIST是控制不同细胞群不同反应的重要分子开关。综上所述，MIST作为免疫受体和细胞因子信号之间的纽带，可以在过敏反应部位增强免疫受体介导的免疫细胞的激活，那里聚集了丰富的细胞因子。因此，抑制MIST的表达和/或功能可能成为抗过敏治疗的潜在靶点，因为MIST缺乏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.