Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
J Immunol. 2013 Oct 1;191(7):3694-704. doi: 10.4049/jimmunol.1300408. Epub 2013 Aug 28.
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 cells (Tregs) are likely to be involved, but through unknown mechanistic pathways. We profiled the transcriptional consequences in CD4(+) Tregs and conventional T cells (Tconvs) 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 Ag-induced responses. Most transcripts were similarly induced in Tregs and Tconvs, but several were differential, in particular, those encoding the IL-7R and transcription factors Id2/3 and Gfi1, upregulated in Tregs but repressed in Tconvs. Because IL-7R was a plausible candidate for driving the homeostatic response of Tregs to anti-CD3, we tested its relevance by supplementation of anti-CD3 treatment with IL-7/anti-IL-7 complexes. Although ineffective alone, IL-7 significantly improved the rate of remission induced by anti-CD3. Four anti-human CD3 mAbs exhibited the same differential effect on IL-7R expression in human as in mouse cells, suggesting that the mechanism also underlies therapeutic effect in human cells, and perhaps a rationale for testing a combination of anti-CD3 and IL-7 for the treatment of recent-onset human type 1 diabetes. Thus, systems-level analysis of the response to anti-CD3 in the early phase of the treatment demonstrates different responses in Tregs and Tconvs, and provides new leads to a mechanistic understanding of its mechanism of action in reverting recent-onset diabetes.
几项临床试验表明，抗 CD3 治疗是治疗自身免疫性糖尿病的一种很有前途的疗法，但它的作用机制仍不清楚。Foxp3(+)调节性 T 细胞（Tregs）可能参与其中，但具体机制尚不清楚。我们对 NOD 小鼠抗 CD3 治疗后最初几小时和几天内 CD4(+)Tregs 和常规 T 细胞（Tconvs）的转录后果进行了分析。抗 CD3 治疗导致短暂的转录反应，比大多数抗原诱导的反应更快终止。大多数转录本在 Tregs 和 Tconvs 中均有相似的诱导，但也有一些差异，特别是编码 IL-7R 以及转录因子 Id2/3 和 Gfi1 的转录本，在 Tregs 中上调，但在 Tconvs 中受到抑制。由于 IL-7R 可能是驱动 Tregs 对抗 CD3 产生同源反应的候选基因，我们通过添加 IL-7/抗 IL-7 复合物来测试其相关性。尽管单独使用无效，但 IL-7 显著提高了抗 CD3 诱导的缓解率。四种抗人 CD3 mAb 在人源和鼠源细胞中对 IL-7R 表达表现出相同的差异效应，这表明该机制也与抗 CD3 治疗人类细胞的疗效有关，也许可以测试抗 CD3 和 IL-7 的联合治疗用于治疗近期发生的人类 1 型糖尿病。因此，对治疗早期抗 CD3 反应的系统水平分析表明，Tregs 和 Tconvs 存在不同的反应，并为深入了解其逆转近期发病糖尿病的作用机制提供了新的线索。
