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

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.

De‐coding genetic risk variants in type 1 diabetes

“…There is a need for additional studies to determine the impact of rs763361 on CD8 + T cell, Treg and NK cell function specifically. In support of this notion, our group has characterized a novel Cd226 knockout (KO) non‐obese diabetic (NOD) mouse strain, observing attenuated T1D onset with reduced peripheral CD8 + T‐cell activation and avidity of the immunodominant islet‐reactive CD8 + T‐cell specificity, islet‐specific glucose‐6‐phosphatase catalytic subunit‐related protein (IGRP) 34 . Our studies of the impact of CD226 on human Treg function showed that CD226 + TIGIT − Tregs lack Helios expression, have reduced suppressive capacity and increased effector cytokine production, 35 suggesting that the deletion of Cd226 may also provide disease protection via enforcement of Treg lineage stability.…”

Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes

“…CD28 binding CD80/CD86, CD27 binding CD70, CD226 binding CD155, OX-40 binding OX-40L, etc.) ( 45 , 46 ). APC such as DC and macrophages serve to initiate T cell responses in the lymph nodes and enhance T cell responses at sites of inflammation.…”

Evaluation of Age-Dependent Immune Signatures in Patients With Multiple Sclerosis

“… 39 , 40 Initially, CD226 was described as a key molecule on proinflammatory Th1-differentiated cells and treatment with an α-CD226 monoclonal antibody reduced the onset and severity of disease in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. 40 In the context of autoimmune diabetes, the knockout of CD226 led to a decreased disease severity in the nonobese diabetes mouse model. 41 In humans, genetic variations of CD226 were linked to a higher susceptibility to develop MS and other autoimmune diseases. 42 These findings, together with our data, imply that CD226 is regulated in an age-dependent manner and plays an important role in modulating autoimmunity.…”