Deficient O-GlcNAc Glycosylation Impairs Regulatory T Cell Differentiation and Notch Signaling in Autoimmune Hepatitis

Abstract

Post-translational modifications such as glycosylation play an important role in the functions of homeostatic proteins, and are critical driving factors of several diseases; however, the role of glycosylation in autoimmune hepatitis is poorly understood. Here, we established an O-GlcNAc glycosylation-deficient rat model by knocking out the <i>Eogt</i> gene by TALEN-mediated gene targeting. O-GlcNAc glycosylation deficiency overtly aggravated liver injury in concanavalin-A induced autoimmune hepatitis, and delayed self-recovery of the liver. Furthermore, flow cytometry analysis revealed increased CD4⁺ T cell infiltration in the liver of rats with O-GlcNAc glycosylation deficiency, and normal differentiation of regulatory T cells (Tregs) in the liver to inhibit T cell infiltration could not be activated. Moreover, <i>in vitro</i> experiments showed that O-GlcNAc glycosylation deficiency impaired Treg differentiation to inhibit the Notch signaling pathway in CD4⁺ T cells. These finding indicate that O-GlcNAc glycosylation plays a critical role in the activation of Notch signaling, which could promote Treg differentiation in the liver to inhibit T cell infiltration and control disease development in autoimmune hepatitis. Therefore, this study reveals a regulatory role for glycosylation in the pathogenesis of autoimmune hepatitis, and highlights glycosylation as a potential treatment target.