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

T细胞上表达的表面分子控制其细胞命运，并提供一种有效的策略来指导免疫反应。为了确定诱导T细胞活化的新的信号成分，定量磷酸蛋白质组学和质谱学已经揭示了SLAMF7是T细胞反应中的一个成分。最初的文献数据是相互矛盾的，SLAMF7在NK细胞中具有激活和抑制功能，在CD8细胞中，它们与耗竭的T细胞和体外培养的T细胞相关，分析了SLAMF7+CD4T细胞表达的细胞毒分子。总体而言，SLAMF7在CD4T细胞反应中的作用尚不清楚。在体外分析T细胞反应，我们有初步证据表明SLAMF7在CD4T细胞亚群上有差异表达。转化生长因子β可抑制其表达。此外，不可知的SLAMF7结合TCR信号表明，SLAMF7可以降低促炎CD4T细胞的增殖起始阈值和细胞因子的产生。从细胞和分子水平了解表面分子SLAMF7在体外和体内对CD4T细胞分化的定量和定性调控是本课题的目的。为此，我们将在感染小鼠模型中使用SLAMF7的遗传失活，通过下拉列表确定SLAMF7结合伙伴，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，并使用多表位配基图谱(Melc)。SLAMF7介导的信号转导在不同CD4亚群的病因学中的作用将从分子和功能细节上确定，以评估SLAMF7对T细胞(再)编程的潜力。此外，SLAMF7介导的CD4T细胞反应的调节将以与其他传统的吸收分子(CTLA-4、PD-1/PDL1、转化生长因子β)相互作用为特征。在本项目的帮助下，我们的目标是全面了解SLAMF7在CD4T细胞分化中的作用。研究结果还将显示SALMF7(或表达SLAMF7的T细胞)是否可以作为病理性免疫反应治疗干预的合适靶分子。

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.