Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes.
Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes.
复制标题
靶向转录辅助调节因子OCA-B/Pou 2af 1阻断胰腺和1型糖尿病中活化的自身反应性T细胞
DOI：
10.1084/jem.20200533
复制
发表时间：
2021-03-01
期刊：
影响因子：
--
通讯作者：
Tantin D
中科院分区：
文献类型：
--
作者：
Kim H;Perovanovic J;Shakya A;Shen Z;German CN;Ibarra A;Jafek JL;Lin NP;Evavold BD;Chou DH;Jensen PE;He X;Tantin D
Kim及其同事表明，T细胞中的OCA-B对1型糖尿病的产生至关重要。OCA-B缺失使胰腺淋巴结基本上不受干扰，但将胰腺中的自身反应性CD 4 + T细胞与无反应性相关联，同时删除潜在的自身反应性CD 8 + T细胞。转录辅助调节因子OCA-B在反复抗原暴露的情况下促进T细胞靶基因的表达，这是自身免疫的必要特征。我们假设T细胞特异性OCA-B缺失和药理学OCA-B抑制可以保护小鼠免受自身免疫性糖尿病的影响。我们开发了一个Ocab条件等位基因，并将其回交到糖尿病易感NOD/ShiLtJ菌株背景上。T细胞特异性OCA-B损失保护小鼠免于自发性疾病。保护作用与糖尿病发病机制相关的胰岛CD 8 + T细胞受体特异性大幅降低有关。存在与糖尿病相关的CD 4+克隆，但与无反应性表型相关。使用自身抗原特异性NY8.3小鼠再现了OCA-B损失的保护作用，但在对人工抗原或新抗原特异性的单克隆模型中减弱。合理设计的膜穿透OCA-B肽抑制剂使新糖尿病NOD小鼠的血糖水平正常化，并减少T细胞浸润和促炎细胞因子表达。总之，结果表明OCA-B是一种有效的自身免疫调节剂，也是一种有希望的药理学抑制靶点。
Kim and colleagues show that OCA-B in T cells is essential for the generation of type 1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells. The transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell–specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell–specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice but diminished in monoclonal models specific to artificial or neoantigens. Rationally designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels and reduced T cell infiltration and proinflammatory cytokine expression in newly diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.
登录
查看更多内容
DOI：
10.1126/science.aad2791
发表时间：
2016-02-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Delong T;Wiles TA;Baker RL;Bradley B;Barbour G;Reisdorph R;Armstrong M;Powell RL;Reisdorph N;Kumar N;Elso CM;DeNicola M;Bottino R;Powers AC;Harlan DM;Kent SC;Mannering SI;Haskins K
通讯作者：
Haskins K
影响因子：
11.1
作者：
Diana J;Lehuen A
通讯作者：
Lehuen A
影响因子：
4.4
作者：
Cantor, Joseph;Haskins, Kathryn
通讯作者：
Haskins, Kathryn
影响因子：
4.4
作者：
Chee, Jonathan;Ko, Hyun-Ja;Krishnamurthy, Balasubramanian
通讯作者：
Krishnamurthy, Balasubramanian
影响因子：
4
作者：
Chevrier, Stephane;Kratina, Tobias;Corcoran, Lynn M.
通讯作者：
Corcoran, Lynn M.