CD226 Deletion Reduces Type 1 Diabetes in the NOD Mouse by Impairing Thymocyte Development and Peripheral T Cell Activation

• Published in: Frontiers in immunology 2020-09, Vol.11, p.2180
• Main Authors: Shapiro, Melanie R, Yeh, Wen-I, Longfield, Joshua R, Gallagher, John, Infante, Caridad M, Wellford, Sarah, Posgai, Amanda L, Atkinson, Mark A, Campbell-Thompson, Martha, Lieberman, Scott M, Serreze, David V, Geurts, Aron M, Chen, Yi-Guang, Brusko, Todd M
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Differentiation, T-Lymphocyte - genetics; Antigens, Differentiation, T-Lymphocyte - metabolism; CD226; CD5 Antigens - genetics; CD5 Antigens - metabolism; CD8+ T cells; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation; Cells, Cultured; costimulatory receptors; Diabetes Mellitus, Type 1 - immunology; Disease Models, Animal; Gene Expression Regulation; Glucose-6-Phosphatase - genetics; Glucose-6-Phosphatase - metabolism; Humans; Immunodominant Epitopes - immunology; Immunologic Memory; Immunology; Lymphocyte Activation; Mice; Mice, Inbred NOD; Mice, Knockout; Peripheral Tolerance; Receptors, Antigen, T-Cell - metabolism; Sjögren’s disease; Thymocytes - immunology; type 1 diabetes
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.02180

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 have been associated with susceptibility to type 1 diabetes and other autoimmune diseases. We hypothesized that genetic deletion of 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.