T细胞受体
细胞生物学
信号转导
蛋白质-蛋白质相互作用
领域(数学分析)
化学
信号蛋白
生物
神经科学
免疫系统
T细胞
免疫学
数学
数学分析
作者
Samuel A. Ritmeester-Loy,Isabelle Draper,Eric Bueter,Jonathan D. Lautz,Yue Zhang-Wong,Joshua A. Gustafson,Ashley Wilson,Chenwei Lin,Philip R. Gafken,Michael C. Jensen,Rimas J. Orentas,Stephen Smith
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2024-03-05
卷期号:17 (826)
标识
DOI:10.1126/scisignal.add4671
摘要
Cells rely on activity-dependent protein-protein interactions to convey biological signals. For chimeric antigen receptor (CAR) T cells containing a 4-1BB costimulatory domain, receptor engagement is thought to stimulate the formation of protein complexes similar to those stimulated by T cell receptor (TCR)-mediated signaling, but the number and type of protein interaction-mediating binding domains differ between CARs and TCRs. Here, we performed coimmunoprecipitation mass spectrometry analysis of a second-generation, CD19-directed 4-1BB:ζ CAR (referred to as bbζCAR) and identified 128 proteins that increased their coassociation after target engagement. We compared activity-induced TCR and CAR signalosomes by quantitative multiplex coimmunoprecipitation and showed that bbζCAR engagement led to the activation of two modules of protein interactions, one similar to TCR signaling that was more weakly engaged by bbζCAR as compared with the TCR and one composed of TRAF signaling complexes that was not engaged by the TCR. Batch-to-batch and interindividual variations in production of the cytokine IL-2 correlated with differences in the magnitude of protein network activation. Future CAR T cell manufacturing protocols could measure, and eventually control, biological variation by monitoring these signalosome activation markers.
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