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

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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10588280/
https://www.ncbi.nlm.nih.gov/pubmed/37625150
http://dx.doi.org/10.2337/db23-0307
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author 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.
author_facet 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.
author_sort Thirawatananond, Puchong
collection PubMed
description 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 (Treg(Δ)(Cd226)) 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.
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spelling pubmed-105882802023-10-21 Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability 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. Diabetes Immunology and Transplantation 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 (Treg(Δ)(Cd226)) 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. American Diabetes Association 2023-11 2023-08-25 /pmc/articles/PMC10588280/ /pubmed/37625150 http://dx.doi.org/10.2337/db23-0307 Text en © 2023 by the American Diabetes Association https://www.diabetesjournals.org/journals/pages/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/journals/pages/license.
spellingShingle Immunology and Transplantation
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.
Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability
title Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability
title_full Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability
title_fullStr Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability
title_full_unstemmed Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability
title_short Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability
title_sort treg-specific cd226 deletion reduces diabetes incidence in nod mice by improving regulatory t-cell stability
topic Immunology and Transplantation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10588280/
https://www.ncbi.nlm.nih.gov/pubmed/37625150
http://dx.doi.org/10.2337/db23-0307
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