Through the catalysis of α2,6-linked sialylation, the enzyme ST6Gal1 is thought to play key roles in immune cell communication and homeostasis. Of particular importance, glycans with terminal α2,6-sialic acids are known to negatively regulate B cell receptor signaling and are associated with an immunosuppressive tumor microenvironment that promotes T cell anergy, suggesting that α2,6-sialic acids are a key immune inhibitory signal. Consistent with this model, mice harboring a hepatocyte-specific ablation of ST6Gal1 (H-cKO) develop a progressive and severe non-alcoholic fatty liver disease characterized by steatohepatitis. Using this H-cKO mouse, we have further discovered that loss of hepatocyte α2,6-sialylation not only increases the inflammatory state of the local tissue microenvironment, but also systemic T cell-dependent immune responses. H-cKO mice responded normally to innate and passively induced inflammation, but showed significantly increased morbidity in T cell-dependent house dust mite-antigen (HDM)-induced asthma and myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis (EAE). We further discovered that H-cKO mice have a profound shift toward effector/memory T cells even among unchallenged mice, and that macrophages from both the liver and spleen expressed the inhibitory and α2,6-sialic acid-specific glycan binding molecule CD22. These findings align with previously reported pro-inflammatory changes in liver macrophages, and support a model in which the liver microenvironment sets a systemic immune tone that is regulated by tissue α2,6-sialylation and mediated by liver macrophages and systemic T cells.

中文翻译：

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肝细胞唾液酸化作用的破坏会驱动T细胞依赖性促炎性免疫调。

通过α2,6-连接的唾液酸化的催化，认为ST6Gal1酶在免疫细胞通讯和体内平衡中起关键作用。尤为重要的是，已知末端带有α2,6-唾液酸的聚糖会负面调节B细胞受体信号传导，并与促进T细胞无反应的免疫抑制性肿瘤微环境有关，这表明α2,6-唾液酸是关键的免疫抑制信号。 。与该模型一致，具有ST6Gal1（H-cKO）肝细胞特异性消融作用的小鼠会发展为进行性且严重的非酒精性脂肪肝，其特征是脂肪性肝炎。使用这种H-cKO小鼠，我们进一步发现肝细胞α2,6-唾液酸化的丧失不仅增加了局部组织微环境的炎症状态，而且还增加了全身性T细胞依赖性免疫反应。H-cKO小鼠对先天性和被动性炎症反应正常，但在依赖T细胞的屋尘螨抗原（HDM）诱导的哮喘和髓磷脂少突胶质细胞糖蛋白（MOG）肽诱导的实验性自身免疫性脑脊髓炎（EAE）中，发病率显着增加。我们进一步发现，H-cKO小鼠甚至在不受挑战的小鼠中也向效应子/记忆T细胞转移，并且来自肝脏和脾脏的巨噬细胞均表达了抑制性和α2,6-唾液酸特异性聚糖结合分子CD22。这些发现与先前报道的肝脏巨噬细胞促炎性变化相符，并支持一种模型，其中肝脏微环境设定了全身免疫调，由组织α2,6-唾液酸化调节，并由肝脏巨噬细胞和全身性T细胞介导。