title: NADPH Oxidase-Derived Superoxide Provides a Third Signal for CD4 T Cell Effector Responses.
abstract: Originally recognized for their direct induced toxicity as a component of the innate immune response, reactive oxygen species (ROS) can profoundly modulate T cell adaptive immune responses. Efficient T cell activation requires: signal 1, consisting of an antigenic peptide-MHC complex binding with the TCR; signal 2, the interaction of costimulatory molecules on T cells and APCs; and signal 3, the generation of innate immune-derived ROS and proinflammatory cytokines. This third signal, in particular, has proven essential in generating productive and long-lasting immune responses. Our laboratory previously demonstrated profound Ag-specific hyporesponsiveness in the absence of NADPH oxidase-derived superoxide. To further examine the consequences of ROS deficiency on Ag-specific T cell responses, our laboratory generated the OT-II.Ncf1(m1J) mouse, possessing superoxide-deficient T cells recognizing the nominal Ag OVA323-339 In this study, we demonstrate that OT-II.Ncf1(m1J) CD4 T cells displayed a severe reduction in Th1 T cell responses, in addition to blunted IL-12R expression and severely attenuated proinflammatory chemokine ligands. Conversely, IFN-γ synthesis and IL-12R synthesis were rescued by the addition of exogenous superoxide via the paramagnetic superoxide donor potassium dioxide or superoxide-sufficient dendritic cells. Ultimately, these data highlight the importance of NADPH oxidase-derived ROS in providing a third signal for adaptive immune maturation by modulating the IL-12/IL-12R pathway and the novelty of the OT-II.Ncf1(m1J) mouse model to determine the role of redox-dependent signaling on effector responses. Thus, targeting ROS represents a promising therapeutic strategy in dampening Ag-specific T cell responses and T cell-mediated autoimmune diseases, such as type 1 diabetes.
authors.affiliation: Department of Microbiology, Comprehensive Diabetes Center, University of Alabama-Birmingham School of Medicine, Birmingham, AL 35294.
authors.forename: Lindsey E
authors.initials: LE
authors.lastname: Padgett
authors.affiliation: Department of Microbiology, Comprehensive Diabetes Center, University of Alabama-Birmingham School of Medicine, Birmingham, AL 35294 htse@uab.edu.
authors.forename: Hubert M
authors.identifier: 0000-0001-5861-7597
authors.initials: HM
authors.lastname: Tse
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism* / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D017382:Reactive Oxygen Species; D053707:Receptors, Interleukin-12; D013481:Superoxides; D018664:Interleukin-12; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1