Inhibition of CD226 co-stimulation suppresses diabetes development in the NOD mouse by augmenting regulatory T cells and diminishing effector T cell function

作者：Matthew E. Brown, Puchong Thirawatananond, Leeana D. Peters, Elizabeth J. Kern, S. Vijay, Lindsey K. Sachs, Amanda L. Posgai, Maigan Brusko, Melanie R. Shapiro, Clayton E. Mathews, Rhonda Bacher, Todd M. Brusko · 发表于：Diabetologia · 年份：2024 · DOI：10.1007/s00125-024-06329-8 · 被引用次数：9 · 研究领域：Diabetes and associated disorders、T-cell and B-cell Immunology、Pancreatic function and diabetes

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. 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. 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...