Thesis Nordin Zandhuis

Abstract

The adaptive immune system protect the host from pathogens and cancer through the actions of B and T lymphocytes.B cells produce antibodies, while CD4⁺ and CD8⁺ T cells secrete effector molecules,including inflammatory cytokines such as Tumor Necrosis Factor (TNF),Interferon gamma (IFN-g), and Interleukin-2 (IL-2). To perform their functions, T and Bcells differentiate into specialized subsets, a process governed by geneexpression programs that are tightly regulated at both transcriptional andpost-transcriptional levels. RNA-binding proteins (RBPs) are keypost-transcriptional regulators that control gene expression by modulating mRNAsplicing, stability, translation, and localization.
This thesis demonstrates that theRBP ZFP36L2 plays a crucial role in limiting IFN-g production duringprolonged T cell activation. ZFP36L2 binds AU-rich elements in the 3’UTR of IfngmRNA, promoting its degradation and thereby reducing IFN-g output. Incontrast, its paralog ZFP36L1 acts earlier during T cell activation, andcombined deletion of ZFP36L1 and ZFP36L2 induces superior cytokine productionin T cells. We further show that ZFP36L1 and ZFP36L2 cooperate to control cellcycle progression and survival in resting T cells. Furthermore, transcriptomicprofiling reveals that RBPs are highly expressed in T and B cells and undergodynamic changes during differentiation. Lastly, we performed a CRISPR-Cas9screen in primary human T cells to identify RBPs that modulate T cellactivation.
Together, the contents of thisthesis underscore the central role of RBPs in T and B cell biology and highlightseveral RBPs as potential targets for modulating T cell function fortherapeutic purposes.