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CD226 Deletion Reduces Type 1 Diabetes in the NOD Mouse by Impairing Thymocyte Development and Peripheral T Cell Activation. Front Immunol 2020;11:2180

Date

10/06/2020

Pubmed ID

33013915

Pubmed Central ID

PMC7500101

DOI

10.3389/fimmu.2020.02180

Scopus ID

2-s2.0-85091212749   2 Citations

Abstract

The costimulatory molecule CD226 is highly expressed on effector/memory T cells and natural killer cells. Costimulatory signals received by T cells can impact both central and peripheral tolerance mechanisms. Genetic polymorphisms in CD226 have been associated with susceptibility to type 1 diabetes and other autoimmune diseases. We hypothesized that genetic deletion of Cd226 in the non-obese diabetic (NOD) mouse would impact type 1 diabetes incidence by altering T cell activation. CD226 knockout (KO) NOD mice displayed decreased disease incidence and insulitis in comparison to wild-type (WT) controls. Although female CD226 KO mice had similar levels of sialoadenitis as WT controls, male CD226 KO mice showed protection from dacryoadenitis. Moreover, CD226 KO T cells were less capable of adoptively transferring disease compared to WT NOD T cells. Of note, CD226 KO mice demonstrated increased CD8+ single positive (SP) thymocytes, leading to increased numbers of CD8+ T cells in the spleen. Decreased percentages of memory CD8+CD44+CD62L- T cells were observed in the pancreatic lymph nodes of CD226 KO mice. Intriguingly, CD8+ T cells in CD226 KO mice showed decreased islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-tetramer and CD5 staining, suggesting reduced T cell receptor affinity for this immunodominant antigen. These data support an important role for CD226 in type 1 diabetes development by modulating thymic T cell selection as well as impacting peripheral memory/effector CD8+ T cell activation and function.

Author List

Shapiro MR, Yeh WI, Longfield JR, Gallagher J, Infante CM, Wellford S, Posgai AL, Atkinson MA, Campbell-Thompson M, Lieberman SM, Serreze DV, Geurts AM, Chen YG, Brusko TM

Authors

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antigens, Differentiation, T-Lymphocyte
CD5 Antigens
CD8-Positive T-Lymphocytes
Cell Differentiation
Cells, Cultured
Diabetes Mellitus, Type 1
Disease Models, Animal
Gene Expression Regulation
Glucose-6-Phosphatase
Humans
Immunodominant Epitopes
Immunologic Memory
Lymphocyte Activation
Mice
Mice, Inbred NOD
Mice, Knockout
Peripheral Tolerance
Receptors, Antigen, T-Cell
Thymocytes