2026-11-03 中国科学院（CAS）
＜関連情報＞
- https://english.cas.cn/newsroom/research-news/202611/t20261103_1213053.shtml
- https://www.pnas.org/doi/10.1073/pnas.2612742123
CD28共刺激はシグナル伝達凝縮体によって組織化され、PD-1によって阻害される CD28 costimulation is organized by signaling condensates and counteracted by PD-1
Hui Chen, Songfang Wu, Yong Zhang, +3 , and Jizhong Lou
Proceedings of the National Academy of Sciences Published:October 21, 2026
DOI:https://doi.org/10.1073/pnas.2612742123
Abstract
T cell activation relies on the coordinated integration of T cell receptor (TCR) and cosignaling pathways, yet how these signals are physically organized remains unclear. Here, we demonstrate that CD28 co-stimulation is driven by a condensation mechanism in which the CD28 intracellular domain (ICD) forms signaling condensates with the Src-family kinase Lck. Ligand engagement promotes CD28 ICD accessibility and triggers rapid CD28/Lck condensation, enhancing CD28 phosphorylation, cytoskeletal polarization, and cytokine production. The downstream effectors of CD28, including PI3K and GRB2, can also be recruited into the CD28-Lck condensates in our reconstituted system. We further identify PD-1 as a graded regulator of this process: Monophosphorylated PD-1 is recruited into CD28/Lck condensates, whereas diphosphorylated PD-1 competitively binds the CD28 ICD and dissolves these assemblies. CD28 and PD-1 ICDs also undergo condensation directly, revealing a dynamic and compositionally heterogeneous signaling system. Guided by this competitive condensation mechanism, we engineer CD28 ICD mutants that preserve Lck condensation while resisting PD-1-mediated disruption. Incorporation of these condensation-selective mutants into Chimeric antigen receptor (CAR) constructs confers resistance to inhibitory signaling and enhances antitumor efficacy in vivo. These findings establish condensation as a central organizing principle of CD28 costimulation and provide a biophysical framework for engineering more resilient therapeutic T cells.
