The role of SLAMF7 (CD319) in the differentiation of CD4+ T-cells

在T细胞上表达的表面分子控制它们的细胞命运，并提供指导免疫应答的有效策略。为了确定T细胞活化后诱导的新的信号传导组分，定量磷酸蛋白质组学和质谱法已经揭示了SLAMF7是T细胞应答中的组分。来自文献的初始数据是矛盾的，SLAMF7可以在NK细胞中执行激活和抑制功能，在CD8细胞中，它们与耗尽的T细胞相关，并且离体分析SLAMF7 + CD4 T细胞表达细胞毒性分子。总体而言，SLAMF7在CD4 T细胞应答中的作用尚不清楚。分析体外T细胞应答，我们有初步证据表明SLAMF7在CD4 T细胞亚群上差异表达。TGF β阻止其表达。此外，与TCR信号传导结合的不可知的SLAMF7接合表明SLAMF7可以降低促炎性CD4 T细胞中增殖和细胞因子产生的起始阈值。本研究的目的是在体外和体内研究表面分子SLAMF7在细胞和分子水平上对CD4 T细胞分化的定量和定性调控。为此，我们将在感染小鼠模型中使用SLAMF7的遗传失活，通过下拉鉴定SLAMF7结合伴侣，并使用修饰的氨基酸进行蛋白质标记来分析SLAMF7介导的翻译组，并采用多表位配体制图（MELC）。将在分子和功能细节上确定SLAMF7介导的信号转导在不同CD4亚群的病因学中的作用，以评估SLAMF7用于T细胞（重）编程的潜力。此外，SLAMF7介导的CD4 T细胞应答调节的特征在于与其他常规抑制性分子（CTLA-4、PD-1/PDL 1、TGF β）的相互作用。在本项目的帮助下，我们的目标是有助于全面了解SLAMF7在CD4 T细胞分化中的作用。结果还将显示SALMF7（或表达SLAMF7的T细胞）是否可以是用于病理性免疫应答中的治疗性干预的合适靶分子。

Surface molecules expressed on T cells control their cell fate and provide an effective strategy to direct immune responses. To determine novel signalling components induced upon T cell activation, quantitative phosphoproteomics and mass spectrometry have revealed that SLAMF7 is a component in T cell responses. Initial data from the literature is contradictory, SLAMF7 can perform both activating and inhibitory functions in NK cells, in CD8 cells, they are associated with exhausted T cells and ex vivo, analysed SLAMF7+ CD4 T cells expressed cytotoxic molecules. Overall, the role of SLAMF7 in CD4 T-cell responses is not understood. Analysing T cell responses in vitro, we have preliminary evidence that SLAMF7 is differentially expressed on CD4 T-cell subpopulations. TGFβ prevents its expression. Furthermore, agnostic SLAMF7 engagement in conjunction with TCR signalling suggests that SLAMF7 can lower the initiation threshold of proliferation and cytokine production in pro-inflammatory CD4 T cells. To understand the quantitative and qualitative control of CD4 T-cell differentiation via the surface molecule SLAMF7 at the cellular and molecular level in vitro and in vivo is the aim of this project. To this end, we will use genetic inactivation of SLAMF7 in an infection mouse model, identify SLAMF7-binding partners by pull-down and analyse the SLAMF7-mediated translatome using modified amino acids for protein labelling, and employ multi-epitope ligand cartography (MELC). The role of SLAMF7-mediated signal transduction in the aetiology of different CD4 subpopulations will be determined in molecular and functional detail to assess the potential of SLAMF7 for T cell (re)programming. Furthermore, SLAMF7-mediated modulation of the CD4 T-cell response will be characterised in interaction with other conventional inbibitory molecules (CTLA-4, PD-1/PDL1, TGFβ). With the help of the present project, we aim to contribute to a comprehensive understanding of the role of SLAMF7 in CD4 T cell differentiation. The results will also show whether SALMF7 (or SLAMF7-expressing T cells) could be a suitable target molecule for therapeutic intervention in pathological immune responses.