De Sousa Linhares Annika, Sharma Sumana, Steinberger Peter, Leitner Judith
Division of Immune Receptors and T Cell Activation, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna, Austria.
Loop lab Bio GmbH, Vienna, Austria.
iScience. 2024 Feb 19;27(3):109267. doi: 10.1016/j.isci.2024.109267. eCollection 2024 Mar 15.
Costimulatory signals provided to T cells during antigen encounter have a decisive role in the outcome of immune responses. Here, we used chimeric receptors harboring the extracellular domain of mouse inducible T cell costimulator (mICOS) to study transcriptional activation mediated by cytoplasmic sequences of the major T cell costimulatory receptors CD28, 4-1BB, and CD2. The chimeric receptors were introduced in a T cell reporter platform that allows to simultaneously evaluate nuclear factor κB (NF-κB), NFAT, and AP-1 activation. Engagement of the chimeric receptors induced distinct transcriptional profiles. CD28 signaling activated all three transcription factors, whereas 4-1BB strongly promoted NF-κB and AP-1 but downregulated NFAT activity. CD2 signals resulted in the strongest upregulation of NFAT. Transcriptome analysis revealed pronounced and distinct gene expression signatures upon CD2 and 4-1BB signaling. Using the intracellular sequence of CD28, we exemplify that distinct signaling motifs endow chimeric receptors with different costimulatory capacities.
抗原接触过程中提供给T细胞的共刺激信号在免疫反应的结果中起决定性作用。在此，我们使用携带小鼠诱导性T细胞共刺激分子（mICOS）胞外结构域的嵌合受体，来研究主要T细胞共刺激受体CD28、4-1BB和CD2的胞质序列介导的转录激活。将嵌合受体引入一个T细胞报告平台，该平台能够同时评估核因子κB（NF-κB）、活化T细胞核因子（NFAT）和活化蛋白-1（AP-1）的激活情况。嵌合受体的结合诱导了不同的转录谱。CD28信号激活了所有三种转录因子，而4-1BB强烈促进NF-κB和AP-1，但下调NFAT活性。CD2信号导致NFAT最强的上调。转录组分析揭示了CD2和4-1BB信号传导后明显且不同的基因表达特征。利用CD28的胞内序列，我们举例说明了不同的信号基序赋予嵌合受体不同的共刺激能力。
