Loss of NOX-Derived Superoxide Exacerbates Diabetogenic CD4 T-Cell Effector Responses in Type 1 Diabetes.
Reactive oxygen species (ROS) play prominent roles in numerous biological systems. While classically expressed by neutrophils and macrophages, CD4 T cells also express NADPH oxidase (NOX), the superoxide-generating multisubunit enzyme. Our laboratory recently demonstrated that superoxide-deficient nonobese diabetic (NOD.Ncf1(m1J)) mice exhibited a delay in type 1 diabetes (T1D) partially due to blunted IFN-γ synthesis by CD4 T cells. For further investigation of the roles of superoxide on CD4 T-cell diabetogenicity, the NOD.BDC-2.5.Ncf1(m1J) (BDC-2.5.Ncf1(m1J)) mouse strain was generated, possessing autoreactive CD4 T cells deficient in NOX-derived superoxide. Unlike NOD.Ncf1(m1J), stimulated BDC-2.5.Ncf1(m1J) CD4 T cells and splenocytes displayed elevated synthesis of Th1 cytokines and chemokines. Superoxide-deficient BDC-2.5 mice developed spontaneous T1D, and CD4 T cells were more diabetogenic upon adoptive transfer into NOD.Rag recipients due to a skewing toward impaired Treg suppression. Exogenous superoxide blunted exacerbated Th1 cytokines and proinflammatory chemokines to approximately wild-type levels, concomitant with reduced IL-12Rβ2 signaling and P-STAT4 (Y693) activation. These results highlight the importance of NOX-derived superoxide in curbing autoreactivity due, in part, to control of Treg function and as a redox-dependent checkpoint of effector T-cell responses. Ultimately, our studies reveal the complexities of free radicals in CD4 T-cell responses.
Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL.
Lindsey E
LE
Padgett
Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL.
Brian
B
Anderson
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL.
Chao
C
Liu
Free Radical Metabolites, Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
Douglas
D
Ganini
Free Radical Metabolites, Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
Ronald P
RP
Mason
Department of Surgery, Immunology, and Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Jon D
JD
Piganelli
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL.
Clayton E
CE
Mathews
Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL htse@uab.edu.
Hubert M
HM
Tse
D056704:Adaptive Immunity; D000818:Animals; D015551:Autoimmunity; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D003433:Crosses, Genetic; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion / Q000009:adverse effects; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D016897:Respiratory Burst; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013481:Superoxides / Q000378:metabolism*
D015415:Biomarkers; D018925:Chemokines; D016207:Cytokines; D013481:Superoxides; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1