Melanie Shapiro laboratory - Treg-Specific CD226 Deletion Reduces

Journal article

P. Thirawatananond, Matthew E Brown, Lindsey K. Sachs, Juan M. Arnoletti, Wen-I Yeh, A. Posgai, Melanie R. Shapiro, Yi-Guang Chen, T. Brusko
Diabetes, 2023

Semantic Scholar DOI PubMedCentral PubMed

Cite

APA Click to copy
Thirawatananond, P., Brown, M. E., Sachs, L. K., Arnoletti, J. M., Yeh, W.-I., Posgai, A., … Brusko, T. (2023). Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability. Diabetes.

Chicago/Turabian Click to copy
Thirawatananond, P., Matthew E Brown, Lindsey K. Sachs, Juan M. Arnoletti, Wen-I Yeh, A. Posgai, Melanie R. Shapiro, Yi-Guang Chen, and T. Brusko. “Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability.” Diabetes (2023).

MLA Click to copy
Thirawatananond, P., et al. “Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability.” Diabetes, 2023.

BibTeX Click to copy

@article{p2023a,
  title = {Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability},
  year = {2023},
  journal = {Diabetes},
  author = {Thirawatananond, P. and Brown, Matthew E and Sachs, Lindsey K. and Arnoletti, Juan M. and Yeh, Wen-I and Posgai, A. and Shapiro, Melanie R. and Chen, Yi-Guang and Brusko, T.}
}

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.