MTOR Regulates Myc-Driven Acinar-to-Dendritic Cell Transition and the CD4 <sup>+</sup> T Cell Immune Response in Acute Pancreatitis

Abstract

Background: The inflammatory response in acute pancreatitis (AP) is associated with acinar-to-dendritic cell transition. The CD4+T cell-mediated adaptive immune response is necessary for pancreatic inflammatory damage. However, the effect of acinar-to-dendritic cell transition on the CD4+T cell response and the regulatory mechanism remain undefined. Methods: An animal model of AP was established by repeated intraperitoneal injection of caerulein. The mTOR inhibitor rapamycin was administered before AP induction. Primary acinar cells were isolated and co-incubated with subsets of differentiated CD4+T cells. Flow cytometry was used to detect the differentiation of naive CD4+T cells. The transcriptional regulatory effect of Myc on DC-SIGN was determined via a luciferase assay. The expression of DC-SIGN was also assessed in pancreatic tissues from human AP patients. Findings: Acinar cells expressed DC-SIGN and displayed the phenotype of dendritic cells (DCs), which promoted the differentiation of naive CD4+T cells into CD4+/IFN-γ+Th1 and CD4+/IL-17A+Th17 cells in pancreatic tissues during AP. DC-SIGN was the target gene of Myc. The mTOR inhibitor rapamycin inhibited AP-induced DC-SIGN expression, CD4+Th1/Th17 cell differentiation and the pro-inflammatory response via Myc. Acinar cells expressed DC-SIGN in pancreatic tissues of human patients with AP. Interpretation: Acinar-to-dendritic cell transition is implicated in the CD4+T cell immune response via the mTOR-Myc-DC-SIGN axis, which might be an effective target for the prevention of local pancreatic inflammation in AP. Funding Statement: This research was financially supported by the Natural Science Foundation of China (Nos. 81270801, 81470941, 81670581 and 8167030165), Program for Outstanding Medical Academic Leader and Shanghai Municipal Science and Technology Commission (No. 18411966400). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: All patient biopsy samples were approved by Ruijin Hospital Ethics Committee. Animal procedures were approved by the Shanghai Jiao Tong University School of Medicine Institutional Animal Care and Use Committee.