CD226 Deletion Reduces Type 1 Diabetes in the NOD Mouse by Impairing Thymocyte Development and Peripheral T Cell Activation.
CD226 Deletion Reduces Type 1 Diabetes in the NOD Mouse by Impairing Thymocyte Development and Peripheral T Cell Activation.
复制标题
DOI：
10.3389/fimmu.2020.02180
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Brusko TM
中科院分区：
文献类型：
--
作者：
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
共刺激分子CD226在效应/记忆T细胞和自然杀伤细胞上高度表达。T细胞接收到的共刺激信号可以影响中枢和外周耐受机制。CD226基因多态性与1型糖尿病和其他自身免疫性疾病的易感性有关。我们假设非肥胖糖尿病(NOD)小鼠中的CD226基因缺失将通过改变T细胞的激活来影响1型糖尿病的发病率。与野生型(WT)对照组相比，CD226基因敲除(KO)NOD小鼠的发病率和岛炎发生率降低。虽然雌性CD226KO小鼠的涎腺炎水平与WT对照组相似，但雄性CD226KO小鼠对泪腺炎有保护作用。此外，与WT nod T细胞相比，CD226KO T细胞过继转移疾病的能力较弱。值得注意的是，CD226 KO小鼠表现出CD8+单一阳性(SP)胸腺细胞的增加，导致脾中CD8+T细胞的数量增加。CD226KO小鼠胰腺淋巴结CD8+CD44+CD62L-T细胞百分率下降。有趣的是，CD226KO小鼠的CD8+T细胞显示胰岛特异性葡萄糖-6-磷酸酶催化亚单位相关蛋白(IGRP)四聚体和CD5染色减少，这表明T细胞受体对这种免疫优势抗原的亲和力降低。这些数据支持CD226通过调节胸腺T细胞选择以及影响外周记忆/效应器CD8+T细胞的激活和功能，在1型糖尿病的发生发展中发挥重要作用。
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.
登录
查看更多内容
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
7.2
作者：
Braun, Matthias;Ress, Marie L.;Woelfl, Matthias
通讯作者：
Woelfl, Matthias
影响因子：
30.8
作者：
Fortune MD;Guo H;Burren O;Schofield E;Walker NM;Ban M;Sawcer SJ;Bowes J;Worthington J;Barton A;Eyre S;Todd JA;Wallace C
通讯作者：
Wallace C
影响因子：
4.4
作者：
Dardalhon, V;Schubart, AS;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
7.3
作者：
Gaud, Guillaume;Roncagalli, Romain;Saoudi, Abdelhadi
通讯作者：
Saoudi, Abdelhadi