Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo.
Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo.
复制标题
DOI：
10.4049/jimmunol.177.7.4376
复制
发表时间：
2006-10-01
期刊：
影响因子：
--
通讯作者：
Powrie F
中科院分区：
文献类型：
--
作者：
Read S;Greenwald R;Izcue A;Robinson N;Mandelbrot D;Francisco L;Sharpe AH;Powrie F
表达CD 25和转录因子FoxP 3的天然存在的CD 4 + TR细胞在免疫稳态中起关键作用，防止对自身和外来抗原的免疫病理反应。CTLA-4由高百分比的这些细胞表达，并且在实验和临床分析中通常被认为是TR的标志物。然而，尚未证明CTLA-4在TR功能中具有直接作用。使用结肠炎转移模型，我们先前表明抗CTLA-4 mAb治疗消除了由CD 4 + CD 25 + TR介导的结肠炎抑制。在这里，我们证明了抗CTLA-4 mAb处理通过对表达CTLA-4的TR细胞的直接作用而不是通过致大肠杆菌性T细胞的过度活化来抑制TR功能。尽管抗CTLA-4 mAb治疗完全抑制TR功能，但其不影响TR细胞扩增、持久性或归巢至肠道相关淋巴组织，表明TR细胞活性所需信号的阻断。与抗体的显著效果相反，CTLA-4缺陷小鼠可以产生功能性TR细胞，这表明可以发展代偿机制。这项研究提供了直接的证据表明，CTLA-4在正常调节性T细胞的功能中具有特异性的、非冗余的作用。当靶向CTLA-4用于治疗目的时，必须考虑这种作用，因为这种策略不仅会增强效应T细胞应答，而且还可能破坏TR介导的自身耐受性。
Naturally occurring CD4+ TR cells that express CD25 and the transcription factor FoxP3 play a key role in immune homeostasis preventing immune pathological responses to self and foreign antigens. CTLA-4 is expressed by a high percentage of these cells, and is often considered as a marker for TR in experimental and clinical analysis. However, it has not yet been proven that CTLA-4 has a direct role in TR function. Using a colitis transfer model, we previously showed that anti-CTLA-4 mAb treatment abrogates suppression of colitis mediated by CD4+ CD25+ TR. Here we demonstrate that anti-CTLA-4 mAb treatment inhibits TR function via direct effects on CTLA-4 expressing TR cells, and not via hyper-activation of colitogenic T cells. Although anti-CTLA-4 mAb treatment completely inhibits TR function, it does not affect TR cell expansion, persistence or homing to the gut-associated lymphoid tissue, indicative of the blockade of a signal required for TR cell activity. In contrast to the striking effect of the antibody, CTLA-4 deficient mice can produce functional TR cells, suggesting that compensatory mechanisms can develop. This study provides direct evidence that CTLA-4 has a specific, non-redundant role in the function of normal regulatory T cells. This role has to be taken into account when targeting CTLA-4 for therapeutic purposes, as such a strategy will not only boost effector T cell responses, but might also break TR-mediated self-tolerance.
登录
查看更多内容
影响因子：
--
作者：
Liu J;Rothermund CA;Ayala-Sanmartin J;Vishwanatha JK
通讯作者：
Vishwanatha JK
影响因子：
30.5
作者：
Fallarino, F;Grohmann, U;Puccetti, P
通讯作者：
Puccetti, P
影响因子：
4.4
作者：
Kataoka, H;Takahashi, S;Saito, T
通讯作者：
Saito, T
影响因子：
30.5
作者：
Grohmann, U;Orabona, C;Puccetti, P
通讯作者：
Puccetti, P
DOI：
10.1084/jem.184.2.783
发表时间：
1996-08-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Karandikar NJ;Vanderlugt CL;Walunas TL;Miller SD;Bluestone JA
通讯作者：
Bluestone JA