IL-2 amplifies quantitative TCR signalling inputs to drive Th1 and Th2 differentiation

IF 4.9 3区 医学 Q2 IMMUNOLOGY Immunology Pub Date : 2024-06-17 DOI:10.1111/imm.13821
Mohammad Ameen Al-Aghbar, Meritxell Espino Guarch, Nicholas van Panhuys
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Abstract

The activation of CD4+ T-cells in a T cell receptor (TCR)-dependent antigen-specific manner is a central characteristic of the adaptive immune response. In addition to ensuring that CD4+ T-cells recognise their cognate antigen during activation, TCR-mediated signalling can also direct the outcome of differentiation. In both in vivo and in vitro model systems, strong TCR signalling has been demonstrated to drive Th1 differentiation, whereas weak TCR signalling drives Th2 responses. During the process of differentiation, TCR signal strength acts as a quantitative component in combination with the qualitative effects imparted by cytokines to polarise distinct T-helper lineages. Here, we investigated the role of interleukin 2 (IL-2) signalling in determining the outcome of TCR-dependent differentiation. IL-2 production was initiated as an early response to TCR-induced activation and was regulated by the strength of TCR signalling initially received. In the absence of IL-2, TCR dependent differentiation was found to be abolished. However, proliferative responses and early markers of activation were maintained, including the upregulation of GATA3, Tbet and Foxp3 at 24 h post-stimulation. Demonstrating that IL-2 signalling has a key role in stabilising and amplifying lineage-specific transcirption factor expression during differentiation. Further, activation of IL-2-deficient T-cells in the presence of exogenous cytokines was sufficient to restore differentiation whilst maintaining transcriptional signatures imparted during initial TCR signalling. Combined, our data demonstrate that the integration of quantitative TCR-dependent signalling and qualitative IL-2 signalling is essential for determining the fate of CD4+ T-cells during differentiation.

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IL-2 放大定量 TCR 信号输入,驱动 Th1 和 Th2 分化。
以 T 细胞受体(TCR)依赖性抗原特异性方式激活 CD4+ T 细胞是适应性免疫反应的核心特征。除了确保 CD4+ T 细胞在活化过程中识别它们的同源抗原外,TCR 介导的信号还能指导分化的结果。在体内和体外模型系统中,已证实强TCR信号可驱动Th1分化,而弱TCR信号可驱动Th2反应。在分化过程中,TCR 信号强度作为一个定量成分与细胞因子的定性效应相结合,极化了不同的 T 辅助系。在这里,我们研究了白细胞介素 2(IL-2)信号在决定 TCR 依赖性分化结果中的作用。IL-2 的产生是对 TCR 诱导的活化的早期反应,并受最初接收到的 TCR 信号强度的调节。在缺乏IL-2的情况下,TCR依赖性分化被取消。然而,增殖反应和早期活化标志物得以维持,包括刺激后24小时GATA3、Tbet和Foxp3的上调。这表明,在分化过程中,IL-2 信号在稳定和扩大细胞系特异性转录因子表达方面起着关键作用。此外,在有外源细胞因子存在的情况下激活 IL-2 缺失的 T 细胞足以恢复分化,同时维持最初 TCR 信号传导过程中的转录特征。我们的数据综合证明,TCR 依赖性定量信号和 IL-2 定性信号的整合对于决定 CD4+ T 细胞在分化过程中的命运至关重要。
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来源期刊
Immunology
Immunology 医学-免疫学
CiteScore
11.90
自引率
1.60%
发文量
175
审稿时长
4-8 weeks
期刊介绍: Immunology is one of the longest-established immunology journals and is recognised as one of the leading journals in its field. We have global representation in authors, editors and reviewers. Immunology publishes papers describing original findings in all areas of cellular and molecular immunology. High-quality original articles describing mechanistic insights into fundamental aspects of the immune system are welcome. Topics of interest to the journal include: immune cell development, cancer immunology, systems immunology/omics and informatics, inflammation, immunometabolism, immunology of infection, microbiota and immunity, mucosal immunology, and neuroimmunology. The journal also publishes commissioned review articles on subjects of topical interest to immunologists, and commissions in-depth review series: themed sets of review articles which take a 360° view of select topics at the heart of immunological research.
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