AUTHOR=Liu Chao , Whitener Robert L. , Lin Andrea , Xu Yuan , Chen Jing , Savinov Alexei , Leiding Jennifer W. , Wallet Mark A. , Mathews Clayton E.
TITLE=Neutrophil Cytosolic Factor 1 in Dendritic Cells Promotes Autoreactive CD8+ T Cell Activation via Cross-Presentation in Type 1 Diabetes
JOURNAL=Frontiers in Immunology
VOLUME=10
YEAR=2019
URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00952
DOI=10.3389/fimmu.2019.00952
ISSN=1664-3224
ABSTRACT=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.