Neutrophil Cytosolic Factor 1 in Dendritic Cells Promotes Autoreactive CD8+ T Cell Activation via Cross-Presentation in Type 1 Diabetes.
Aims: Reactive oxygen species (ROS) are critical in driving the onset of type 1 diabetes (T1D). Ablation of ROS derived from phagocytic NADPH oxidase 2 is protective against autoimmune diabetes in non-obese diabetic (NOD) mice. However, the mechanisms of NADPH oxidase 2-derived ROS in T1D pathogenesis need to be elucidated. Here, we have examined the role of Ncf1 (the regulatory subunit of NADPH oxidase 2) in dendritic cells (DC). Results: Ncf1-mutant DCs exhibit reduced ability to activate autoreactive CD8+ T cells despite no difference in co-stimulatory molecule expression or pro-inflammatory cytokine production. When provided with exogenous whole-protein antigen, Ncf1-mutant NOD DCs showed strong phagosome acidification and rapid antigen degradation, which lead to an absence of protein translocation into the cytoplasm and deficient antigenic peptide loading on MHC Class I molecules. Innovation: This study demonstrates that Ncf1 (p47phox) is required for activation and effector function of CD8+ T cells by acting both intrinsically within the T cell as well as within professional antigen presenting cells. Conclusion: ROS promote CD8+ T cell activation by facilitating autoantigen cross-presentation by DCs. ROS scavengers could potentially represent an important component of therapies aiming to disrupt autoantigen presentation and activation of CD8+ T cells in individuals at-risk for developing T1D.
['Liu|Chao|C|', 'Whitener|Robert L|RL|', 'Lin|Andrea|A|', 'Xu|Yuan|Y|', 'Chen|Jing|J|', 'Savinov|Alexei|A|', 'Leiding|Jennifer W|JW|', 'Wallet|Mark A|MA|', 'Mathews|Clayton E|CE|']
D000818:Animals D015551:Autoimmunity D018414:CD8-Positive T-Lymphocytes D045142:Cross-Priming D003713:Dendritic Cells D003922:Diabetes Mellitus, Type 1 D008213:Lymphocyte Activation D051379:Mice D016688:Mice, Inbred NOD D008817:Mice, Mutant Strains D019255:NADPH Oxidases
dendritic cell CD8+ T cell cross-presentation type 1 diabetes Reactive oxygen species NADPH oxidase 2 Ncf1