Arifin Muhammad Zainul, Leitner Judith, Egan Donagh, Waidhofer-Söllner Petra, Kolch Walter, Zhernovkov Vadim, Steinberger Peter
Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna, Austria.
iScience. 2024 Jun 12;27(7):110253. doi: 10.1016/j.isci.2024.110253. eCollection 2024 Jul 19.
T cell co-inhibitory immune checkpoints, such as PD-1 or BTLA, are bona fide targets in cancer therapy. We used a human T cell reporter line to measure transcriptomic changes mediated by PD-1- and BTLA-induced signaling. T cell receptor (TCR)-complex stimulation resulted in the upregulation of a large number of genes but also in repression of a similar number of genes. PD-1 and BTLA signals attenuated transcriptomic changes mediated by TCR-complex signaling: upregulated genes tended to be suppressed and the expression of a significant number of downregulated genes was higher during PD-1 or BTLA signaling. BTLA was a significantly stronger attenuator of TCR-complex-induced transcriptome changes than PD-1. A strong overlap between genes that were regulated indicated quantitative rather than qualitative differences between these receptors. In line with their function as attenuators of TCR-complex-mediated changes, we found strongly regulated genes to be prime targets of PD-1 and BTLA signaling.
T细胞共抑制性免疫检查点，如PD-1或BTLA，是癌症治疗中的真正靶点。我们使用一种人类T细胞报告系来测量由PD-1和BTLA诱导的信号传导介导的转录组变化。T细胞受体（TCR）复合物刺激导致大量基因上调，但也导致数量相近的基因被抑制。PD-1和BTLA信号减弱了由TCR复合物信号传导介导的转录组变化：上调的基因倾向于被抑制，并且在PD-1或BTLA信号传导期间，大量下调基因的表达更高。与PD-1相比，BTLA是TCR复合物诱导的转录组变化的更强衰减剂。受调控基因之间存在强烈重叠，表明这些受体之间存在数量而非质量上的差异。与它们作为TCR复合物介导变化的衰减剂的功能一致，我们发现受强烈调控的基因是PD-1和BTLA信号传导的主要靶点。
