- Walking the wire
- Post-transcriptional regulation of T cell effector functions in health and disease
R.A.W. van Lier
- Award date
- 2 February 2018
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Memory T cells protect us from recurring infections by rapidly releasing pro-inflammatory cytokines. However, high levels of cytokines can be highly toxic. Thus, their release must be tightly regulated to guarantee a protective yet balanced immune response. Here, we show that post-transcriptional regulation is critical to modulate the cytokine production of T cells.
We show that memory T cells use pre-formed mRNA for immediate cytokine production in response to recall infections. In the absence of infection, however, the constitutively expressed mRNA must be silenced to avoid immunopathology. We found that this block in translation is an active process and that the RNA-binding protein ZFP36L2 binds to AU-rich elements (AREs) on cytokine mRNAs, thereby preventing their recruitment to ribosomes. Upon T cell activation, ZFP36L2 rapidly releases the cytokine mRNA, which can immediately be used as template for protein production. In effector T cells, post-transcriptional events dictate the duration and magnitude of cytokine production depending on the cues a T cell receives.
Post-transcriptional regulation can also impair T cell effector functions. For instance, tumor-infiltrating T cells gradually lose their capacity to produce cytokines. We demonstrated that the mere removal of AREs from the Interferon gamma mRNA was sufficient to restore the cytokine production, which significantly improved the anti-tumoral response. We therefore postulate that altering post-transcriptional events can be exploited for therapeutic purposes.
In conclusion, we show that post-transcriptional regulation of cytokines is a highly dynamic process. AREs are crucial elements herein to guarantee optimal T cell function.
Thesis (complete) (Embargo up to and including 2 February 2020)
Chapter 2: Translational repression of pre-formed cytokine mRNA prevents chronic activation of memory T cells (Embargo up to and including 2 February 2020)
Chapter 5: Costimulation through TLR2 and TLR7 augments cytokine production of CD8+ T cells (Embargo up to and including 2 February 2020)
Chapter 6: Critical role of post-transcriptional regulation for IFN-γ in tumor-infiltrating T cells (Embargo up to and including 2 February 2020)
Chapter 7: General discussion (Embargo up to and including 2 February 2020)
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