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DB23-0307 CD226_cKO_Supplemental_Figures_(Revision).pdf (3.55 MB)

Treg-specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T Cell Stability

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posted on 2023-08-25, 20:41 authored by Puchong Thirawatananond, Matthew E. Brown, Lindsey K. Sachs, Juan M. Arnoletti, Wen-I Yeh, Amanda L. Posgai, Melanie R. Shapiro, Yi-Guang Chen, Todd M. Brusko

Co-stimulation serves as a critical checkpoint for T cell activation, and several genetic variants affecting co-stimulatory pathways confer risk for autoimmune diseases. A single nucleotide polymorphism (rs763361) in the CD226 gene encoding a co-stimulatory receptor increases susceptibility to multiple autoimmune diseases, including type 1 diabetes. We previously found that Cd226 knockout protected non-obese diabetic (NOD) mice from disease, but the impact of CD226 on individual immune subsets remained unclear. Our prior reports implicate regulatory T cells (Treg), as human CD226+ Tregs exhibit reduced suppressive function. Hence, we hypothesized that genomic Cd226 gene deletion would increase Treg stability, and 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 (TregCd226) strain that displayed decreased insulitis and diabetes incidence. CD226-deficient pancreatic Tregs had increased expression of the co-inhibitory counter-receptor TIGIT. Moreover, NOD splenocytes treated with a TIGIT-Fc fusion protein exhibited reduced T cell proliferation and IFN-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 co-stimulatory pathway to halt autoimmunity.


Keywords: CD226, NOD mouse, regulatory T cell, type 1 diabetes, conditional knockout, Treg stability

Highlights

· We previously found that Cd226 genomic knockout in NOD mice reduced insulitis severity and diabetes incidence, but the impact on individual immune subsets remained unclear.

· Human CD226+ Tregs exhibit reduced suppressive function suggesting Cd226 gKO would increase Treg stability, and Treg-specific Cd226 deletion would inhibit diabetes in NOD.

· Treg-conditional CD226 KO reduced insulitis and delayed diabetes onset in female NOD mice while CD226 gKO NODs displayed reduced ex-Tregs in pancreas and increased TIGIT expression on Tregs.

CD226/TIGIT imbalance contributes to Treg instability in NOD mice and highlights the potential for therapeutic targeting this co-stimulatory pathway in type 1 diabetes.

Funding

Diabetes Research Connection Project #45

Juvenile Diabetes Research Foundation United States of America 3-PDF-2022-1137-A-N

U.S. Department of Health and Human Services > National Institutes of Health > National Institute of Diabetes and Digestive and Kidney Diseases F30 DK128945 R01 DK106191

The Leona M. and Harry B. Helmsley Charitable Trust x 2004-03813

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