CYBB/NOX2 in conventional DCs controls T cell encephalitogenicity during neuroinflammation

Whereas central nervous system (CNS) homeostasis is highly dependent on tissue surveillance by immune cells, dysregulated entry of leukocytes during autoimmune neuroinflammation causes severe immunopathology and neurological deficits. To invade the CNS parenchyma, encephalitogenic T helper (T-H) cells must encounter their cognate antigen(s) presented by local major histocompatibility complex (MHC) class II-expressing antigen-presenting cells (APCs). The precise mechanisms by which CNS-associated APCs facilitate autoimmune T cell reactivation remain largely unknown. We previously showed that mice with conditional deletion of the gene encoding the essential autophagy protein ATG5 in dendritic cells (DCs) are resistant to EAE development. Here, we report that the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2, also known as CYBB/NOX2, in conventional DCs (cDCs) regulates endocytosed MOG (myelin oligodendrocyte protein) antigen processing and supports MOG-antigen presentation to CD4(+) T cells through LC3-associated phagocytosis (LAP). Genetic ablation of Cybb in cDCs is sufficient to restrain encephalitogenic T-H cell recruitment into the CNS and to ameliorate clinical disease development upon the adoptive transfer of MOG-specific CD4(+) T cells. These data indicate that CYBB-regulated MOG-antigen processing and LAP in cDCs licenses encephalitogenic T-H cells to initiate and sustain autoimmune neuroinflammation.

Automated summary

This study reveals that the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 in conventional dendritic cells (cDCs) regulates MOG antigen processing through LC3-associated phagocytosis (LAP), enabling encephalitogenic T helper cells to initiate and sustain autoimmune neuroinflammation. Genetic ablation of Cybb in cDCs restrains T-H cell recruitment into the CNS and ameliorates clinical disease development upon the adoptive transfer of MOG-specific CD4(+) T cells.