Brady Alexander E, Revu Shankar, Wu Dongwen, Fisk Hannah, Kone Khadija, Lydecker Alexandria, Purser Elliott J, Smith Norah, Hilt Zachary T, Woodyear Sarah, Caddy Sarah, Gingras Sebastien, Rudd Brian, McGeachy Mandy M
Cornell University, Ithaca NY, USA.
University of Pittsburgh, Pittsburgh PA, USA.
bioRxiv. 2025 Mar 13:2025.03.10.642460. doi: 10.1101/2025.03.10.642460.
CD28 ligation provides critical signals that modulate activated T cell fate. In a human to mouse reverse-engineering approach, a single amino acid substitution adjacent to the C-terminal proline-rich domain created CD28 mice with enhanced signaling. CD28 mice experienced pro-inflammatory responses to CD28 superagonist antibody, analogous to severe cytokine storm induced in a human clinical trial, with a striking increase of activated CD8 T cells. In acute and chronic viral infections, early activation and expansion of CD28 CD8 effector T cells increased, with accelerated exhaustion in chronic infection. Mechanistically, CD28 enhanced JunB, IL-2, and inhibitory receptors driven by MEK1/2. Generation of CD28 stem-like progenitor (Tpex) cells was enhanced in acute and chronic infections, and further expanded by PD-L1 blockade in chronically-infected mice. Thus, 'humanized' PYAP mice reveal key roles for CD28 signaling strength in CD8 activation, accelerating exhaustion during antigen persistence, while promoting and sustaining Tpex during acute and chronic viral infection.
CD28 连接提供调节活化 T 细胞命运的关键信号。在一种人源到小鼠的逆向工程方法中，靠近 C 末端富含脯氨酸结构域的单个氨基酸取代产生了具有增强信号传导的 CD28 小鼠。CD28 小鼠对 CD28 超激动剂抗体产生促炎反应，类似于在一项人类临床试验中诱导的严重细胞因子风暴，活化的 CD8 T 细胞显著增加。在急性和慢性病毒感染中，CD28 CD8 效应 T 细胞的早期活化和扩增增加，在慢性感染中耗竭加速。从机制上讲，CD28 增强了由 MEK1/2 驱动的 JunB、IL-2 和抑制性受体。在急性和慢性感染中，CD28 样干细胞祖细胞（Tpex）的生成增强，并且在慢性感染的小鼠中通过 PD-L1 阻断进一步扩增。因此，“人源化”的 PYAP 小鼠揭示了 CD28 信号强度在 CD8 活化中的关键作用，在抗原持续存在期间加速耗竭，同时在急性和慢性病毒感染期间促进和维持 Tpex。
