RORyt+CD4+ T cells promote IL-23R-mediated neuronal cell apoptosis in the central nervous system

Transcription factors T-bet and ROR{psi}t play a crucial role in neuronal autoimmunity, and mice deficient in these two factors do not develop experimental autoimmune encephalomyelitis (EAE). The independent role of T-bet and ROR{psi}t in the pathogenesis of EAE and how they help induce apoptosis of neurons in the central nervous system (CNS) during neuronal autoimmunity is unclear. In the present study, we showed that myelin oligodendrocyte glycoprotein (MOG35-55) peptide-specific Th1 cells deficient in ROR{psi}t could cross BBB but fail to induce apoptosis of neurons and EAE. Pathogenic Th17 cell-derived cytokines GM-CSF, TNF-, IL-17A, and IL-21 significantly increase the surface expression of IL-23R on neuronal cells. Furthermore, we showed that, in EAE, neurons in the brain and spinal cord express IL-23R. IL-23-IL-23R signaling in neuronal cells caused phosphorylation of STAT3 (Ser727 and Tyr705) and induced cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase-1 (PARP-1) molecules in an IL-23R-dependent manner and caused apoptosis. Thus, we provided a mechanism where we showed that T-bet is required to recruit pathogenic Th17 cells and ROR{psi}t expression to drive the apoptosis of IL-23R+ neurons in the CNS and cause EAE. Understanding detailed molecular mechanisms will help to design better strategies to control neuroinflammation and autoimmunity. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/537133v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@2586b0org.highwire.dtl.DTLVardef@1adb3deorg.highwire.dtl.DTLVardef@fbce53org.highwire.dtl.DTLVardef@1a6d4ae_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryIL-23-IL-23R signaling promotes apoptosis of CNS neurons.