The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway.
The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway.
复制标题
DOI：
10.3389/fimmu.2012.00190
复制
发表时间：
2012
影响因子：
7.3
通讯作者：
Sitkovsky M
中科院分区：
文献类型：
--
作者：
Ohta A;Kini R;Ohta A;Subramanian M;Madasu M;Sitkovsky M
A2A型腺苷受体(A2AR)介导的免疫抑制在抗病原体免疫反应中对侧支组织损伤的救命下调和在抗肿瘤免疫反应中对肿瘤组织的高度不良保护中被明确地涉及。因此，根据具体的临床情况，有必要减弱或增强A2AR信号的强度。虽然A2AR介导的免疫抑制在效应性T细胞的研究中被证明是T细胞自主的，但A2AR刺激如何影响调节性T细胞(Treg)尚不清楚。我们在平行实验中发现，虽然A2AR对T细胞的刺激直接抑制T细胞的激活，但也有间接的和更持久的T细胞抑制作用通过Treg的调节。A2AR刺激在FoxP3+细胞中扩增了CD4+CD25，同时也表达CD39、CD73和CTLA-4。与A2AR激动剂共同培养的Treg细胞CTLA-4表达增加，免疫抑制活性增强。A2AR刺激后Treg细胞数量明显增加。CD_4~+FoxP_3~+细胞主要来源于CD_4~+CD_(25+)−细胞。因此，A2AR的刺激在数值上和功能上增强了Treg介导的免疫抑制机制。这些数据表明，在将Treg转移到不同医疗应用的患者之前，在体外扩增Treg的方案中应考虑A2AR介导的使用A2AR激动剂刺激淋巴细胞。
The A2A adenosine receptor (A2AR)-mediated immunosuppression is firmly implicated in the life-saving down-regulation of collateral tissue damage during the anti-pathogen immune response and in highly undesirable protection of cancerous tissues during anti-tumor immune response. Therefore, depending on specific clinical situation there is a need to either weaken or strengthen the intensity of A2AR signal. While the A2AR-mediated immunosuppression was shown to be T cell autonomous in studies of effector T cells, it was not clear how A2AR stimulation affects regulatory T cells (Treg). Here we show in parallel assays that while A2AR stimulation on T cells directly inhibits their activation, there is also indirect and longer-lasting T cell inhibitory effect through modulation of Treg. A2AR stimulation expanded CD4+ CD25hi FoxP3+ cells, which also express CD39, CD73, and CTLA-4. Treg cultured with A2AR agonist showed increased expression of CTLA-4 and stronger immunosuppressive activity. There was a significant increase of Treg cell number after A2AR stimulation. The CD4+ FoxP3+ population contained those induced from CD4+ CD25− cells, but CD4+ FoxP3+ cells predominantly derived from CD4+ CD25+ natural Treg. Thus, A2AR stimulation numerically and functionally enhanced Treg-mediated immunosuppressive mechanism. These data suggest that the A2AR-mediated stimulation of lymphocytes using A2AR agonists should be considered in protocols for ex vivo expansion of Treg before the transfer to patients in different medical applications.
登录
查看更多内容
DOI：
10.1084/jem.161.1.72
发表时间：
1985-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sakaguchi S;Fukuma K;Kuribayashi K;Masuda T
通讯作者：
Masuda T
影响因子：
5.4
作者：
Hoffmann, Petra;Boeld, Tina J.;Edinger, Matthias
通讯作者：
Edinger, Matthias
影响因子：
4.4
作者：
Pouliot, M;Fiset, MÉ;Borgeat, P
通讯作者：
Borgeat, P
影响因子：
4
作者：
Cadieux, JS;Leclerc, P;Pouliot, M
通讯作者：
Pouliot, M
DOI：
10.1073/pnas.0605251103
发表时间：
2006-08-29
影响因子：
11.1
作者：
Ohta, Akio;Gorelik, Elieser;Sitkovsky, Michail
通讯作者：
Sitkovsky, Michail