Modulation of Redox Balance Leaves Murine Diabetogenic TH1 T Cells “LAG-3-ing” Behind

  1. Jon D. Piganelli1,2
  1. 1Diabetes Institute, Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  2. 2Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  3. 3Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee
  1. Corresponding author: Jon D. Piganelli, jdp51{at}pitt.edu.

Abstract

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 3, 2012.

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  1. Diabetes vol. 61 no. 7 1760-1768
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