Year: 2012
Type: article
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.
Source: Diabetes
DOI: 10.2337/db11-1591
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Awards: G1291335382, G2484743557, Mechanism and function of the regulatory protein LAG-3, G5054099725, G5389863958, G5775912428, G609259107, MULTIMOLECULAR INTERACTIONS DURING TCR RECOGNITION, G782193539, Autoimmunity and Immunopathology Training Program, G9000086855, Cancer Center Support Grant (CCSG)
OpenAlex ID: W2124620436