Ma Victor Pui-Yan, Hu Yuesong, Kellner Anna V, Brockman Joshua M, Velusamy Arventh, Blanchard Aaron T, Evavold Brian D, Alon Ronen, Salaita Khalid
Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta, GA 30332, USA.
Sci Adv. 2022 Feb 25;8(8):eabg4485. doi: 10.1126/sciadv.abg4485.
T cells defend against cancer and viral infections by rapidly scanning the surface of target cells seeking specific peptide antigens. This key process in adaptive immunity is sparked upon T cell receptor (TCR) binding of antigens within cell-cell junctions stabilized by integrin (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) complexes. A long-standing question in this area is whether the forces transmitted through the LFA-1/ICAM-1 complex tune T cell signaling. Here, we use spectrally encoded DNA tension probes to reveal the first maps of LFA-1 and TCR forces generated by the T cell cytoskeleton upon antigen recognition. DNA probes that control the magnitude of LFA-1 force show that >12 pN potentiates antigen-dependent T cell activation by enhancing T cell-substrate engagement. LFA-1/ICAM-1 mechanical events with >12 pN also enhance the discriminatory power of the TCR when presented with near cognate antigens. Overall, our results show that T cells integrate multiple channels of mechanical information through different ligand-receptor pairs to tune function.
T细胞通过快速扫描靶细胞表面寻找特定的肽抗原，来抵御癌症和病毒感染。适应性免疫中的这一关键过程，是在整合素（淋巴细胞功能相关抗原-1，LFA-1）/细胞间黏附分子-1（ICAM-1）复合物稳定的细胞间连接处，T细胞受体（TCR）与抗原结合后引发的。该领域长期存在的一个问题是，通过LFA-1/ICAM-1复合物传递的力是否会调节T细胞信号传导。在此，我们使用光谱编码的DNA张力探针，揭示了抗原识别后T细胞细胞骨架产生的LFA-1和TCR力的首张图谱。控制LFA-1力大小的DNA探针显示，大于12皮牛（pN）的力通过增强T细胞与底物的结合，增强了抗原依赖性T细胞的激活。当面对近同源抗原时，大于12 pN的LFA-1/ICAM-1机械事件也增强了TCR的辨别能力。总体而言，我们的结果表明，T细胞通过不同的配体-受体对整合多个机械信息通道来调节功能。
