Silencing of PD-L2/B7-DC by Topical Application of Small Interfering RNA Inhibits Elicitation of Contact Hypersensitivity

Abstract

Abstract PD-L2 is a ligand for the immune checkpoint receptor PD-1, however, its regulatory function is unclear. We previously reported that silencing of CD86 in cutaneous dendritic cells (DCs) by topical siRNA application inhibits the elicitation of contact hypersensitivity (CHS). Here we investigated the effects of topical PD-L2 siRNA application on allergic skin disease. PD-L2 was induced in DCs concurrently with the elevation of MHC class II and CD86 expression. Topical PD-L2 siRNA application inhibited elicitation of CHS by suppressing early proinflammatory cytokine expression and migration of hapten-carrying DCs into lymph nodes. Local injection of neutralizing anti-PD-L2 mAb comparably inhibited CHS. PD-L2 siRNA treatment inhibited the CHS in PD-1/PD-L1 double-knockout mice and in the sensitized T-cell-transferred skin. These results suggest that the effects of PD-L2 silencing are independent of PD-1 but dependent on local memory T cells. Most of the inhibitory effects of PD-L2 and CD86 silencing on CHS were comparable, but PD-L2 siRNA treatment did not inhibit atopic disease-like manifestations and Th2 responses in NC/Nga mice. Our results suggest that PD-L2 in cutaneous DCs acts as a costimulator rather than a regulator. Local PD-L2 silencing by topical siRNA application represents a new therapeutic approach for contact allergy.