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

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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.