Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability. Diabetes 2023 Nov 01;72(11):1629-1640
Date
08/25/2023Pubmed ID
37625150Pubmed Central ID
PMC10588280DOI
10.2337/db23-0307Scopus ID
2-s2.0-85175068629 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
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.
Author List
Thirawatananond P, Brown ME, Sachs LK, Arnoletti JM, Yeh WI, Posgai AL, Shapiro MR, Chen YG, Brusko TMAuthor
Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntigens, Differentiation, T-Lymphocyte
Diabetes Mellitus, Type 1
Female
Forkhead Transcription Factors
Mice
Mice, Inbred NOD
Mice, Knockout
Pancreas
Receptors, Immunologic
T-Lymphocytes, Regulatory
