Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Sci Signal. 2020 Dec 8;13(661):eaba9600. doi: 10.1126/scisignal.aba9600.
Regulatory T cells (T cells) restrict immune system activity, such as in response to self-antigens, and are switched on by tumor necrosis factor receptor 2 (TNFR2). Therapeutic activation of TNFR2, thereby expanding T cells and suppressing immune activity, may be beneficial to patients with various inflammatory diseases. Here, we characterized a new human TNFR2-directed antibody agonist isolated from mice. We found that the antibody agonist expanded the number of T cells within cultures of primary human CD4 T cells from healthy donors and patients with type 1 diabetes or Sézary syndrome. These T cells had increased metabolic gene expression and intracellular itaconate concentrations, characteristics associated with maximally suppressive, anti-inflammatory T cells. Furthermore, antibody-expanded T cells repressed the activity of primary human CD8 effector T cells (T cells). Epitope mapping suggested that the antibody bound to TNFR2 through a natural cross-linking surface and that T cell expansion was independent of the antibody Fc region. In addition, T cell expansion was not increased by adding either supplemental TNF ligand or a cross-linking reagent, suggesting that the antibody agonist by itself can elicit maximal activity, a notion that was confirmed by increased secretion of soluble TNFR2. Pending in vivo tests, these features indicate that this TNFR2 antibody agonist has the potential to safely and effectively treat various inflammatory disorders.
调节性 T 细胞（T 细胞）限制免疫系统的活动，例如对自身抗原的反应，并且由肿瘤坏死因子受体 2（TNFR2）激活。TNFR2 的治疗性激活，从而扩增 T 细胞并抑制免疫活性，可能对患有各种炎症性疾病的患者有益。在这里，我们从小鼠中分离出一种新的人类 TNFR2 定向抗体激动剂进行了表征。我们发现，该抗体激动剂扩增了来自健康供体和 1 型糖尿病或蕈样真菌病患者的原代人 CD4 T 细胞培养物中的 T 细胞数量。这些 T 细胞具有增加的代谢基因表达和细胞内衣康酸浓度，这是与最大抑制、抗炎 T 细胞相关的特征。此外，抗体扩增的 T 细胞抑制了原代人 CD8 效应 T 细胞（T 细胞）的活性。表位作图表明，抗体通过天然交联表面与 TNFR2 结合，并且 T 细胞扩增不依赖于抗体 Fc 区。此外，添加补充的 TNF 配体或交联试剂并不能增加 T 细胞的扩增，这表明抗体激动剂本身就可以发挥最大活性，这一观点通过可溶性 TNFR2 的增加分泌得到了证实。在进行体内测试之前，这些特征表明这种 TNFR2 抗体激动剂具有安全有效地治疗各种炎症性疾病的潜力。
