Metabolic blockade of glycolysis diminishes autoreactive CD4 T cell differentiation in Type 1 diabetes 4521
Year: 2025
Type: article
Abstract: Description Type 1 diabetes (T1D) is a result of pancreatic β-cell destruction by autoreactive T cells. Proinflammatory Th1 CD4 T cells prefer glycolysis for maintaining effector responses. We hypothesize that metabolic inhibition of glycolysis will diminish Th1 CD4 T cell responses and delay β-cell destruction. Systemic treatment of non-obese diabetic (NOD) mice with 2-deoxyglucose (2-DG) via drinking water significantly delayed spontaneous T1D (p < 0.05) compared to control mice (n = 25 per group). Ex vivo stimulation of pancreatic lymph node CD4 T cells from 2-DG-treated NOD mice, had a significant (p < 0.01) decrease in T-bet expression, a key Th1 transcription factor, compared to control. To define the molecular mechanisms of 2-DG on autoreactive CD4 T cell effector responses, NOD.BDC-6.9 splenocytes were stimulated in vitro with their cognate hybrid insulin peptide (HIP; insulin C-peptide and islet amyloid polypeptide) with or without 2-DG. Flow cytometry analysis revealed a significant decrease in T cell proliferation (Ki67) and T-bet expression. IFN-γ was also significantly (p < 0.05) decreased following 2-DG treatment compared to controls. In addition to murine models, human PBMCs stimulated with Dynabeads and 2-DG had a decrease in IFNG and TBET compared to controls. Diminishing glycolysis in autoreactive T cells delayed diabetes and Th1 effector responses. Future studies will investigate the effects of 2-DG on the metabolic profile during CD4 T cell differentiation in T1D. Funding Sources 5T32GM8111-35 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)
Source: The Journal of Immunology
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416446512
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