Post-transcriptional regulation of effector function in T cells by RNA binding proteins

Project Information

PRinTERs

Grant agreement ID: 817533

DOI

10.3030/817533

Project closed

EC signature date 28 February 2019

Start date 1 March 2019

End date 31 August 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 000 000,00

EU contribution

€ 2 000 000,00

Coordinated by

Stichting Sanquin Bloedvoorziening
Netherlands

Periodic Reporting for period 4 - PRinTERs (Post-transcriptional regulation of effector function in T cells by RNA binding proteins)

Reporting period: 2023-09-01 to 2024-08-31

Summary of the context and overall objectives of the project

CD8+ T cells are critical to fight infections and to clear tumor cells. When they recognize their target cells, CD8+ T cells produce inflammatory cytokines and cytotoxic molecules. The production of these effector molecules must be well controlled: too little leads to the inability to control the pathogen, and too much can result in a life-threatening cytokine storm and tissue damage. A pivotal regulatory mechanism that defines the actual protein output in cells is post-transcriptional regulation (PTR). PTR determines the generation and the fate of messenger RNA, and the translation efficiency. RNA binding proteins (RBPs) are key modulators of these processes. However, to date the analysis of RBPs in modulating T cell effector function is anecdotal and focused on a few of the >2000 putative RBPs. A systematic analysis on RBP expression in T cells is to date lacking, yet key to define how PTR drives T cell effector function, and to define targets that help boost T cell responses against cancers.
Here, we have identified the RBP repertoire in primary human T cells. With state-of-the-art approaches we have determined how RBPs imprint the effector function of human CD8+ T cells. We have uncovered how RBP expression and interactions alter upon T cell activation, and we defined how these changes drive T cell responses. We have also revealed how RBPs can imprint and/or maintain the killer phenotype of human CD8+ T cells. Identifying these mechanisms should help to identify therapeutic targets to boost the cytotoxic potency of T cell products against e.g. cancers.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Here, we have identified the RBP repertoire in primary human T cells, shown how the RBP binding alters upon T cell activation. Specifically, our study has uncovered the time-dependency and cell type/cell state specificity of mode of action of RBPs, highlighting the intricate regulation of fine tuning T cell effetor function. We have uncovered novel insights in the fate of cytokine T cells by providing information on subcellular localization of cytokine mRNA during the course of T cell activation. We will also define how RBPs can imprint and/or maintain the killer phenotype of human CD8+ T cells. Identifying these mechanisms should help to identify therapeutic targets to boost the cytotoxic potency of T cell products against e.g. cancers.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

By developing state-of-the-art toolboxes, we have uncovered the RBP landscape in T cells and how it changes upon T cell activation. We have uncovered novel mechanisms how translation control is mediated in T cells, which will yield new possibilities in manipulating T cell responses in health and disease.

scheme-erc.png