Intravenous tolerance induces T cell anergy/apoptosis via IFN-γ/IL-27/PD-L1 axis

Abstract

Abstract The induction of peripheral tolerance by intravenous injection (i.v.) of auto-Ags has shown to suppress experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis, by eliciting tolerogenic APCs, Tregs, and suppressing self-reactive T cells. The programmed cell death protein (PD)-1 and its ligands, PD-L1 and PD-L2, regulate the balance between T cell activation and immune tolerance. Although PD-L1 and PD-L2 are expressed on a variety of cell types, however, the mechanisms related to peripheral tolerance that induce these molecules are still unclear. Here we show that PD-L1, but not PD-L2, is critical for inducing peripheral tolerance in EAE, and that PD-L1-dependent tolerance relies on both IFN-γ and IL-27. I.v. administration of auto-Ag(s) attenuates the progression of EAE, by inducing PD-L1 expression in monocyte-derived DCs (moDCs) in the CNS, via IFN-γ/ IL-27-dependent mechanism. Indeed, when PD-L1 is blocked, autoantigen(s)/i.v treatment becomes ineffective. Following IFN-γ−/− CD4+ T cell transfer into Rag1−/− mice, i.v. tolerance treatment failed to suppress EAE. Moreover, loss of IFN-γR signaling in classical DCs type I (cDCs I) compromised IL-27 production and consequent PD-L1 expression by moDCs. We also show that IL-27 stimulates moDCs to over-express PD-L1, in a STAT-3-dependent way. Indeed, in CCR2−/−/WSX−/− (CD45.2) → CD45.1 radiation-induced bone marrow chimera mice, auto-Ag(s)/i.v. treatment failed to suppress EAE. Similarly, EAE mice that expressed mutant STAT-3 (muSTAT-3) in CCR2+ cells were also insensitive to i.v. tolerance induction. Our data reveal a mechanism whereby IFN-γ and IL-27 are the key factors in PD-L1 induction and subsequent peripheral tolerance restoration.