Activation of T cell checkpoint pathways during β-cell antigen presentation by engineered dendritic cells promotes protection from type 1 diabetes.
Activation of T cell checkpoint pathways during β-cell antigen presentation by engineered dendritic cells promotes protection from type 1 diabetes.
复制标题
作者：
Defective immune regulation has been recognized in type 1 diabetes (T1D). Immune regulatory T cell check-point receptors, which are generally upregulated on activated T cells, have been the molecules of attention as therapeutic targets for enhancing immune response in tumor therapy. Here, we show that pancreatic β-cell antigen (BcAg) presentation by engineered tolerogenic dendritic cells (tDCs) that express CTLA4 selective ligand (B7.1wa) or a combination of CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1, and HVEM-CRD1 respectively; multiligand-DCs) causes an increase in regulatory cytokine and T cell (Treg) responses and suppression of the effector T cell function as compared to engineered control-DCs. Non-obese diabetic (NOD) mice treated with BcAg-pulsed CTLA4-ligand-DCs and multiligand-DCs at pre-diabetic and early-hyperglycemic stages showed significantly lower degree of insulitis, higher frequencies of insulin-positive islets, profound delay in, and reversal of, hyperglycemia for a significant duration. Immune cells from the tDC treated mice not only produced lower amounts of IFNγ and higher amounts of IL10 and TGFβ1 upon BcAg challenge, but also failed to induce hyperglycemia upon adoptive transfer. While both CTLA4-ligand-DCs and multiligand-DCs were effective in inducing tolerance, multiligand-DC treatment produced an overall higher suppressive effect on effector T cell function and disease outcome. These studies show that enhanced engagement of T cell checkpoint receptors during BcAg presentation can modulate T cell function and suppress autoimmunity and progression of the disease in T1D.
登录
查看更多内容
T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.5
作者：
Besche, Verena;Wiechmann, Nadine;Bros, Matthias
通讯作者：
Bros, Matthias
影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
影响因子：
16.8
作者：
Croft, M
通讯作者：
Croft, M
影响因子：
4.4
作者：
Li, Ruobing;Perez, Nicolas;Vasu, Chenthamarakshan
通讯作者：
Vasu, Chenthamarakshan