Modulation of redox balance leaves murine diabetogenic TH1 T cells "LAG-3-ing" behind.

Diabetes
Meghan M DelmastroJon D Piganelli

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...Continue Reading

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Citations

May 21, 2013·Antioxidants & Redox Signaling·Meghan M Delmastro-GreenwoodJon D Piganelli
Mar 12, 2013·Antioxidants & Redox Signaling·Meghan M Delmastro-GreenwoodJon D Piganelli
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Oct 11, 2017·Antioxidants & Redox Signaling·Dana M Previte, Jon D Piganelli
Apr 27, 2019·Annals of the New York Academy of Sciences·Tijana Martinov, Brian T Fife
Jun 25, 2019·ESMO Open·Hannah Christina Puhr, Aysegül Ilhan-Mutlu
Jul 31, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lindsey E Padgett, Hubert M Tse
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Aug 14, 2020·International Journal of Hematology·Yingying SunZonghong Shao
Jun 3, 2021·International Journal of Molecular Sciences·Luisa ChocarroDavid Escors
Jun 25, 2021·Frontiers in Immunology·Christina P MartinsJon D Piganelli

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Methods Mentioned

BETA
flow cytometry
enzyme–linked immunosorbent assays
ELISA
ELISAs
enzyme-linked immunosorbent spot
protein assay
immunoprecipitation
GTPases

Software Mentioned

Multi Gauge
FlowJo
SoftMax Pro

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