Modulation of Redox Balance Leaves Murine Diabetogenic TH1 T Cells “LAG-3-ing” Behind
- Meghan M. Delmastro1,2,
- Alexis J. Styche1,
- Massimo M. Trucco1,2,
- Creg J. Workman3,
- Dario A.A. Vignali3 and
- Jon D. Piganelli1,2⇓
- 1Diabetes Institute, Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- 2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- 3Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Corresponding author: Jon D. Piganelli, .
Preventing activation of diabetogenic T cells is critical for delaying type 1 diabetes onset. The inhibitory molecule lymphocyte activation gene 3 (LAG-3) and metalloprotease tumor necrosis factor-α converting enzyme (TACE) work together to regulate TH1 responses. The aim of this study was to determine if regulating redox using a catalytic antioxidant (CA) could modulate TACE-mediated LAG-3 shedding to impede diabetogenic T-cell activation and progression to disease. A combination of in vitro experiments and in vivo analyses using NOD mouse strains was conducted to test the effect of redox modulation on LAG-3 shedding, TACE enzymatic function, and disease onset. Systemic treatment of NOD mice significantly delayed type 1 diabetes onset. Disease prevention correlated with decreased activation, proliferation, and effector function of diabetogenic T cells; reduced insulin-specific T-cell frequency; and enhanced LAG-3+ cells. Redox modulation also affected TACE activation, diminishing LAG-3 cleavage. Furthermore, disease progression was monitored by measuring serum soluble LAG-3, which decreased in CA-treated mice. Therefore, affecting redox balance by CA treatment reduces the activation of diabetogenic T cells and impedes type 1 diabetes onset via decreasing T-cell effector function and LAG-3 cleavage. Moreover, soluble LAG-3 can serve as an early T-cell–specific biomarker for type 1 diabetes onset and immunomodulation.
- Received November 15, 2011.
- Accepted March 2, 2012.
- © 2012 by the American Diabetes Association.
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