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

Periodic Reporting for period 2 - PRinTERs (Post-transcriptional regulation of effector function in T cells by RNA binding proteins)

Reporting period: 2020-09-01 to 2022-02-28

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 will identify the RBP repertoire in primary human T cells. With state-of-the-art approaches we will determine how RBPs imprint the effector function of human CD8+ T cells. We will uncover alterations of RBP expression upon T cell activation and define how these changes drive T cell responses. 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.
We have now obtained first insights in the RBP repertoire. We show that RBP expression is cell-type specific and alters upon differentiation of T cells. We also found that depletion of some RBPs in primary human T cells results in altered expression profile of effector molecules. Importantly deleting one of these RBPs improved the anti-tumoral response of T cells in vivo. We are currently further interrogating the role of RBPs on the function of T cells in health and disease.
We expect to reveal the mechanisms that define the cytokine production of T cells, and that thus define the T cell effector function in health and disease.