APA
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Brown, M. E., Thirawatananond, P., Peters, L. D., Kern, E. J., Vijay, S., Sachs, L. K., … Brusko, T. M. (2024). Inhibition of CD226 co-stimulation suppresses diabetes development in the NOD mouse by augmenting regulatory T cells and diminishing effector T cell function. Diabetologia.
Chicago/Turabian
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Brown, Matthew E, P. Thirawatananond, Leeana D. Peters, Elizabeth J Kern, Sonali Vijay, Lindsey K. Sachs, A. Posgai, et al. “Inhibition of CD226 Co-Stimulation Suppresses Diabetes Development in the NOD Mouse by Augmenting Regulatory T Cells and Diminishing Effector T Cell Function.” Diabetologia (2024).
MLA
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Brown, Matthew E., et al. “Inhibition of CD226 Co-Stimulation Suppresses Diabetes Development in the NOD Mouse by Augmenting Regulatory T Cells and Diminishing Effector T Cell Function.” Diabetologia, 2024.
BibTeX Click to copy
@article{matthew2024a,
title = {Inhibition of CD226 co-stimulation suppresses diabetes development in the NOD mouse by augmenting regulatory T cells and diminishing effector T cell function},
year = {2024},
journal = {Diabetologia},
author = {Brown, Matthew E and Thirawatananond, P. and Peters, Leeana D. and Kern, Elizabeth J and Vijay, Sonali and Sachs, Lindsey K. and Posgai, A. and Brusko, Maigan A. and Shapiro, Melanie R. and Mathews, Clayton E. and Bacher, Rhonda L. and Brusko, Todd M.}
}
Aims/hypothesis Immunotherapeutics targeting T cells are crucial for inhibiting autoimmune disease progression proximal to disease onset in type 1 diabetes. There is an outstanding need to augment the durability and effectiveness of T cell targeting therapies by directly restraining proinflammatory T cell subsets, while simultaneously augmenting regulatory T cell (Treg) activity. Here, we present a novel strategy for preventing diabetes incidence in the NOD mouse model using a blocking monoclonal antibody targeting the type 1 diabetes risk-associated T cell co-stimulatory receptor, CD226. Methods Female NOD mice were treated with anti-CD226 at 7–8 weeks of age and then monitored for diabetes incidence and therapeutic mechanism of action. Results Compared with isotype-treated controls, anti-CD226-treated NOD mice showed reduced insulitis severity (0.84-fold, p=0.0002) at 12 weeks and decreased disease incidence (HR 0.41, p=0.015) at 30 weeks. Flow cytometric analysis performed 5 weeks post treatment demonstrated reduced proliferation of conventional CD4+ T cells (0.87-fold, p=0.030) and CD8+ (0.78-fold, p=0.0018) effector memory T cells in spleens of anti-CD226-treated mice. Phenotyping of pancreatic Tregs revealed increased CD25 expression (2.05-fold, p=0.0073) and signal transducer and activator of transcription 5 (STAT5) phosphorylation (1.39-fold, p=0.0007) following anti-CD226, with splenic Tregs displaying augmented suppression of CD4+ responder T cells (Tresps) (1.49-fold, p=0.0008, 1:2 Treg:Tresp) in vitro. Anti-CD226-treated mice exhibited reduced frequencies of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive CD8+ T cells in the pancreas, using both ex vivo tetramer staining (0.50-fold, p=0.0317) and single-cell T cell receptor sequencing (0.61-fold, p=0.022) approaches. 51Cr-release assays demonstrated reduced cell-mediated lysis of beta cells (0.61-fold, p<0.0001, 1:1 effector:target) by anti-CD226-treated autoreactive cytotoxic T lymphocytes. Conclusions/interpretation CD226 blockade reduces T cell cytotoxicity and improves Treg function, representing a targeted and rational approach for restoring immune regulation in type 1 diabetes. Graphical Abstract Supplementary Information The online version of this article (10.1007/s00125-024-06329-8) contains peer-reviewed but unedited supplementary material.