Differential response of regulatory and conventional CD4⁺ lymphocytes to CD3 engagement: clues to a possible mechanism of anti-CD3 action?
Differential response of regulatory and conventional CD4⁺ lymphocytes to CD3 engagement: clues to a possible mechanism of anti-CD3 action?
复制标题
DOI：
10.4049/jimmunol.1300408
复制
发表时间：
2013-10-01
期刊：
影响因子：
--
通讯作者：
Benoist C
中科院分区：
文献类型：
--
作者：
Li L;Nishio J;van Maurik A;Mathis D;Benoist C
一些临床试验表明，抗CD3治疗是一种有希望的自身免疫性糖尿病治疗方法，但其作用机制尚不清楚。Foxp3+调节性T(Treg)细胞可能参与其中，但机制未知。我们描述了NOD小鼠在抗CD3治疗后的最初几个小时和几天内，CD4+Treg和传统T(Tconv)细胞的转录结果。抗CD3抗体治疗导致了短暂的转录反应，终止的速度比大多数抗原诱导的反应更快。大多数转录本在Treg和Tconv细胞中诱导类似，但有几个是不同的，特别是编码IL7受体(IL7R)和转录因子Id2/3和Gfi1的转录本，在Treg中上调，但在Tconv细胞中抑制。由于IL7R是驱动Treg细胞对抗CD3的动态平衡反应的一个可能的候选者，我们通过用IL7/抗IL7复合体补充抗CD3治疗来检验其相关性。尽管IL7单独无效，但显著提高了抗CD3抗体诱导的缓解率。四种抗人CD3单抗在人和小鼠细胞中对IL7R表达的差异显示出相同的作用，这表明这一机制也是人类细胞治疗效果的基础，也可能是测试抗CD3和IL7组合治疗新近发病的人类1型糖尿病(T1D)的基础。因此，对治疗早期抗CD3反应的系统水平分析在Treg和Tconv细胞中显示了不同的反应，并为从机制上理解其逆转新近发病的糖尿病的作用机制提供了新的线索。
Several clinical trials have shown anti-CD3 treatment to be a promising therapy for autoimmune diabetes, but its mechanism of action remains unclear. Foxp3+ regulatory T (Treg) cells are likely to be involved, but through unknown mechanistic pathways. We profiled the transcriptional consequences in CD4+ Treg and conventional T (Tconv) cells in the first hours and days after anti-CD3 treatment of NOD mice. Anti-CD3 treatment led to a transient transcriptional response, terminating faster than most antigen-induced responses. Most transcripts were similarly induced in Treg and Tconv cells, but several were differential, in particular those encoding the IL7 receptor (IL7R) and transcription factors Id2/3 and Gfi1, upregulated in Treg but repressed in Tconv cells. As IL7R was a plausible candidate for driving the homeostatic response of Treg cells to anti-CD3, we tested its relevance by supplementation of anti-CD3 treatment with IL7/anti-IL7 complexes. Although ineffective alone, IL7 significantly improved the rate of remission induced by anti-CD3. Four anti-human CD3 mAbs exhibited the same differential effect on IL7R expression in human as in mouse cells, suggesting that the mechanism also underlie therapeutic effect in human cells, and perhaps a rationale for testing a combination of anti-CD3 and IL7 for the treatment of recent-onset human type-1 diabetes (T1D). Thus, systems level analysis of the response to anti-CD3 in the early phase of the treatment demonstrates different responses in Treg and Tconv cells, and provides new leads to a mechanistic understanding of its mechanism of action in reverting recent-onset diabetes.
登录
查看更多内容
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
64.8
作者：
Esplugues, Enric;Huber, Samuel;Gagliani, Nicola;Hauser, Anja E.;Town, Terrence;Wan, Yisong Y.;O'Connor, William, Jr.;Rongvaux, Anthony;Van Rooijen, Nico;Haberman, Ann M.;Iwakura, Yoichiro;Kuchroo, Vijay K.;Kolls, Jay K.;Bluestone, Jeffrey A.;Herold, Kevan C.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
DOI：
10.4049/jimmunol.181.1.225
发表时间：
2008-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bayer AL;Lee JY;de la Barrera A;Surh CD;Malek TR
通讯作者：
Malek TR
影响因子：
4.4
作者：
Chandele, Anmol;Joshi, Nikhil S.;Kaech, Susan M.
通讯作者：
Kaech, Susan M.
DOI：
10.1084/jem.20051409
发表时间：
2005-11-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen Z;Herman AE;Matos M;Mathis D;Benoist C
通讯作者：
Benoist C