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

Informazioni relative al progetto

PRinTERs

ID dell’accordo di sovvenzione: 817533

DOI

10.3030/817533

Progetto chiuso

Data della firma CE 28 Febbraio 2019

Data di avvio 1 Marzo 2019

Data di completamento 31 Agosto 2024

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 2 000 000,00

Contributo UE

€ 2 000 000,00

Coordinato da

Stichting Sanquin Bloedvoorziening
Netherlands

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

Periodo di rendicontazione: 2023-09-01 al 2024-08-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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.

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