Porciello Nicla, Grazioli Paola, Campese Antonio F, Kunkl Martina, Caristi Silvana, Mastrogiovanni Marta, Muscolini Michela, Spadaro Francesca, Favre Cédric, Nunès Jacques A, Borroto Aldo, Alarcon Balbino, Screpanti Isabella, Tuosto Loretta
Department of Biology and Biotechnology Charles Darwin, Laboratory Affiliated at Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185, Rome, Italy.
Department of Experimental Medicine, Sapienza University, 00161, Rome, Italy.
Nat Commun. 2018 Mar 14;9(1):1080. doi: 10.1038/s41467-018-03385-8.
CD28 superagonistic antibodies (CD28SAb) can preferentially activate and expand immunosuppressive regulatory T cells (Treg) in mice. However, pre-clinical trials assessing CD28SAbs for the therapy of autoimmune diseases reveal severe systemic inflammatory response syndrome in humans, thereby implying the existence of distinct signalling abilities between human and mouse CD28. Here, we show that a single amino acid variant within the C-terminal proline-rich motif of human and mouse CD28 (P in human vs. A in mouse) regulates CD28-induced NF-κB activation and pro-inflammatory cytokine gene expression. Moreover, this YAPP sequence in humans is crucial for the association of CD28 with the Nck adaptor protein for actin cytoskeleton reorganisation events necessary for CD28 autonomous signalling. This study thus unveils different outcomes between human and mouse CD28 signalling to underscore the importance of species difference when transferring results from preclinical models to the bedside.
CD28超激动剂抗体（CD28SAb）可优先激活并扩增小鼠体内的免疫抑制性调节性T细胞（Treg）。然而，评估CD28SAb用于自身免疫性疾病治疗的临床前试验显示，人类会出现严重的全身炎症反应综合征，这意味着人类和小鼠的CD28存在不同的信号传导能力。在此，我们表明，人类和小鼠CD28的C末端富含脯氨酸基序内的单个氨基酸变体（人类为P，小鼠为A）调节CD28诱导的NF-κB激活和促炎细胞因子基因表达。此外，人类的这种YAPP序列对于CD28与Nck衔接蛋白的结合至关重要，而Nck衔接蛋白参与了CD28自主信号传导所需的肌动蛋白细胞骨架重组事件。因此，本研究揭示了人类和小鼠CD28信号传导的不同结果，以强调将临床前模型的结果转化至临床应用时物种差异的重要性。
