Vitamin A deficiency enhances susceptibility to experimental autoimmune pancreatitis through activation of CD4+ T cells expressing CXCR3 and secreting CCL25.

Abstract

Conventional dendritic cells (cDCs) in the gut express the vitamin A (VA)-converting enzyme retinal dehydrogenase 2 (RALDH2) and produce significant amounts of retinoic acid (RA). RA derived from gut cDCs contributes to the generation of tolerogenic responses by promoting regulatory T-cell (Treg) differentiation while inhibiting Th1 and Th17 cell differentiation. In this study, we investigated whether similar RA-mediated immunoregulatory mechanisms operate in the pancreas using an experimental autoimmune pancreatitis (AIP) model. Our previous studies have shown that activated cDCs and plasmacytoid DCs (pDCs) play crucial roles in the induction and maturation phases of experimental AIP, respectively. Pancreatic cDCs produce IFN-α/β, CXCL9, and CXCL10, which attract CD4+CXCR3+ T cells to the pancreas during the induction phase. These CD4+CXCR3+ T cells, in turn, produce CCL25, recruiting CCR9+ pDCs that secrete IFN-α/β, CXCL9, and CXCL10 during the maturation phase. Under homeostatic conditions, RALDH2 expression was higher in pancreatic cDCs than in pDCs. Pancreatic cDCs isolated from VA-deficient mice promoted CD4+ T-cell production of IFN-γ and CCL25-the latter being a chemokine implicated in AIP pathogenesis. VA deficiency increased susceptibility to experimental AIP through a process dependent on the pancreatic accumulation of CD4+CXCR3+ T cells producing CCL25. Conversely, activation of RA-mediated signaling pathways by Am80 protected mice from severe AIP by reducing the accumulation of CXCR3+ T cells producing CCL25. Collectively, these findings suggest that RA produced by cDCs protects against AIP development by inhibiting the pancreatic accumulation of CD4+CXCR3+ T cells. RA-mediated immunoregulation may serve as a potential therapeutic target for AIP.