title: Modulation of redox balance leaves murine diabetogenic TH1 T cells "LAG-3-ing" behind.
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.
authors.affiliation: National Institute for Health Research Comprehensive Biomedical Research Centre at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London, London, UK.
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Delmastro
authors.forename: Alexis J
authors.initials: AJ
authors.lastname: Styche
authors.forename: Massimo M
authors.initials: MM
authors.lastname: Trucco
authors.forename: Creg J
authors.initials: CJ
authors.lastname: Workman
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
authors.forename: Jon D
authors.initials: JD
authors.lastname: Piganelli
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D015703:Antigens, CD / Q000097:blood / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D008213:Lymphocyte Activation / Q000187:drug effects; D008345:Manganese / Q000494:pharmacology*; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D010084:Oxidation-Reduction; D013482:Superoxide Dismutase / Q000494:pharmacology*; D018417:Th1 Cells / Q000187:drug effects* / Q000378:metabolism; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D008665:Metalloporphyrins; D008345:Manganese; D013482:Superoxide Dismutase; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse