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- Title
Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability.
- Authors
Thirawatananond, Puchong; Brown, Matthew E.; Sachs, Lindsey K.; Arnoletti, Juan M.; Yeh, Wen-I; Posgai, Amanda L.; Shapiro, Melanie R.; Chen, Yi-Guang; Brusko, Todd M.
- Abstract
Costimulation serves as a critical checkpoint for T-cell activation, and several genetic variants affecting costimulatory pathways confer risk for autoimmune diseases. A single nucleotide polymorphism (rs763361) in the CD226 gene encoding a costimulatory receptor increases susceptibility to multiple autoimmune diseases, including type 1 diabetes. We previously found that Cd226 knockout protected NOD mice from disease, but the impact of CD226 on individual immune subsets remained unclear. Our prior reports implicate regulatory T cells (Tregs), as human CD226+ Tregs exhibit reduced suppressive function. Hence, we hypothesized that genomic Cd226 gene deletion would increase Treg stability and that Treg-specific Cd226 deletion would inhibit diabetes in NOD mice. Indeed, crossing NOD.Cd226−/− and a NOD Treg-lineage tracing strain resulted in decreased pancreatic Foxp3-deficient "ex-Tregs." We generated a novel Treg-conditional knockout (TregΔCd226) strain that displayed decreased insulitis and diabetes incidence. CD226-deficient pancreatic Tregs had increased expression of the coinhibitory counter-receptor T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT). Moreover, NOD splenocytes treated with TIGIT-Fc fusion protein exhibited reduced T-cell proliferation and interferon-γ production following anti-CD3/CD28 stimulation. This study demonstrates that a CD226/TIGIT imbalance contributes to Treg instability in NOD mice and highlights the potential for therapeutic targeting this costimulatory pathway to halt autoimmunity. Article Highlights: We previously found that Cd226 genomic knockout (gKO) in NOD mice reduced insulitis severity and diabetes incidence, but the impact on individual immune subsets remained unclear. Human CD226+ regulatory T cells (Tregs) exhibit reduced suppressive function, suggesting Cd226 gKO would increase Treg stability, and Treg-specific Cd226 deletion would inhibit diabetes in NOD mice. Treg-conditional Cd226 KO reduced insulitis and delayed diabetes onset in female NOD mice, while Cd226 gKO NOD mice displayed reduced Foxp3-deficient Tregs in pancreas and increased T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) expression on Tregs. CD226/TIGIT imbalance contributes to Treg instability in NOD mice and highlights the potential for therapeutic targeting this costimulatory pathway in type 1 diabetes.
- Subjects
AUTOIMMUNE diseases; CD28 antigen; REGULATORY T cells; T cells; TYPE 1 diabetes; SINGLE nucleotide polymorphisms; MICE
- Publication
Diabetes, 2023, Vol 72, Issue 11, p1629
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db23-0307