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J Immunol. 2016 Sep 1;197(5):1733-42. doi: 10.4049/jimmunol.1502581. Epub 2016 Jul 29.

NADPH Oxidase-Derived Superoxide Provides a Third Signal for CD4 T Cell Effector Responses.

Author information

1
Department of Microbiology, Comprehensive Diabetes Center, University of Alabama-Birmingham School of Medicine, Birmingham, AL 35294.
2
Department of Microbiology, Comprehensive Diabetes Center, University of Alabama-Birmingham School of Medicine, Birmingham, AL 35294 htse@uab.edu.

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.

PMID:
27474077
PMCID:
PMC4992601
DOI:
10.4049/jimmunol.1502581
[Indexed for MEDLINE]
Free PMC Article

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