Adenosine Receptor 2A Agonist-Induced Tolerogenic Dendritic Cells Protect Mouse Kidney from Ischemia-Reperfusion Injury (52.2)

Abstract

Dendritic cell (DC)-mediated nature killer T (NKT) cell activation is critical in initiating the immune response following kidney ischemia-reperfusion injury (IRI). Adenosine 2A receptor (A2AR) agonists protect kidneys from IRI through their actions on bone marrow (BM)-derived leukocytes. We hypothesized that A2AR agonists attenuate IRI by tolerizing DCs and preventing NKT cell activation. ATL313 attenuated kidney IRI in WT mice but not in mice deficient of DC A2ARs (CD11c-CreAdora2a-/-). BM-derived DCs were activated by ex vivo incubation with alpha-galactosylceramide (aGC)±ATL313 (1nM), washed and adoptively transferred into naïve WT mice 2 days before kidney IRI. ATL313-treated aGC-loaded WT DCs (DC-aGC-ATL313) but neither Adora2a-/- DC-aGC-ATL313 nor DC-aGC protected kidney function following IRI. Co-culture of NKT cells with DC-aGC-ATL313 caused less IFN-g production than with DC-aGC. ATL313 down-regulated OX40L and CD40 and up-regulated B7-DC expression but had no effect on DC surface and intracellular CD1d/aGC complexes. DC-aGC-ATL313-mediated kidney protection was not due to Treg cell expansion, but was in part due to IL-10, as IL-10mRNA level increased and IL-10 neutralization reversed the protective effect of DC-aGC-ATL313; DC-aGC-ATL313 also up-regulated PD-1 expression on co-cultured Tregs. We conclude that A2AR-induced tolerized DCs, which suppressed NKT cell activation in vivo, provide a unique and potent cell-based strategy to attenuate organ IRI.