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Disruption of Innate-Mediated Proinflammatory Cytokine and Reactive Oxygen Species Third Signal Leads to Antigen-Specific Hyporesponsiveness¹

Diabetes Institute, Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213

Successful Ag activation of naive T helper cells requires at least two signals consisting of TCR and CD28 on the T cell interacting with MHC II and CD80/CD86, respectively, on APCs. Recent evidence demonstrates that a third signal consisting of proinflammatory cytokines and reactive oxygen species (ROS) produced by the innate immune response is important in arming the adaptive immune response. In an effort to curtail the generation of an Ag-specific T cell response, we targeted the synthesis of innate immune response signals to generate Ag-specific hyporesponsiveness. We have reported that modulation of redox balance with a catalytic antioxidant effectively inhibited the generation of third signal components from the innate immune response (TNF-, IL-1, ROS). In this study, we demonstrate that innate immune-derived signals are necessary for adaptive immune effector function and disruption of these signals with in vivo CA treatment conferred Ag-specific hyporesponsiveness in BALB/c, NOD, DO11.10, and BDC-2.5 mice after immunization. Modulating redox balance led to decreased Ag-specific T cell proliferation and IFN- synthesis by diminishing ROS production in the APC, which affected TNF- levels produced by CD4⁺ T cells and impairing effector function. These results demonstrate that altering redox status can be effective in T cell-mediated diseases such as autoimmune diabetes to generate Ag-specific immunosuppression because it inhibits the third signal necessary for CD4⁺ T cells to transition from expansion to effector function.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Cochrane-Weber research award (to H.M.T.), a Research Advisory Council Postdoctoral Fellowship Award by Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center Health System (to H.M.T.), a Research Advisory Council Award (to J.P.), an American Diabetes Association Junior Faculty Award (to J.P.), and a Juvenile Diabetes Research Foundation Research Grant (to J.P.).

² Address correspondence and reprint requests to Dr. Jon D. Piganelli, Diabetes Institute, Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213-3205. E-mail address: jdp51{at}pitt.edu

³ Abbreviations used in this paper: LN, lymph node; CA, catalytic antioxidant; ROS, reactive oxygen species; MnTDE, Mn(III) 5,10,15,20-tetrakis(N,N'-diethylimidazolium-2-yl)porphyrin; MnTE₂, Mn(III) 5,10,15,20-tetrakis(N-ethylpyridinium-2- yl)porphyrin; DC, dendritic cell; HEL, hen egg lysozyme; PCC, pigeon cytochrome c; IHC, immunohistochemistry; RA, rheumatoid arthritis; CM-H₂DCFDA, 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; MAMP, microbial-associated molecular pattern; MFI, mean fluorescence intensity; TACE, TNF- convertase; T-bet, Th1-specific T box transcription factor.

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