Post‐transcriptional control of T‐cell cytokine production: Implications for cancer therapy

Abstract

As part of the adaptive immune system, T cells are vital for the eradication of infected and malignantly transformed cells. To perform their protective function, T cells produce effector molecules that are either directly cytotoxic, such as granzymes, perforin, interferon‐γ and tumour necrosis factor α, or attract and stimulate (immune) cells, such as interleukin‐2. As these molecules can also induce immunopathology, tight control of their production is required. Indeed, inflammatory cytokine production is regulated on multiple levels. Firstly, locus accessibility and transcription factor availability and activity determine the amount of mRNA produced. Secondly, post‐transcriptional mechanisms, influencing mRNA splicing/codon usage, stability, decay, localization and translation rate subsequently determine the amount of protein that is produced. In the immune suppressive environments of tumours, T cells gradually lose the capacity to produce effector molecules, resulting in tumour immune escape. Recently, the role of post‐transcriptional regulation in fine‐tuning T‐cell effector function has become more appreciated. Furthermore, several groups have shown that exhausted or dysfunctional T cells from cancer patients or murine models possess mRNA for inflammatory mediators, but fail to produce effector molecules, hinting that post‐transcriptional events also play a role in hampering tumour‐infiltrating lymphocyte effector function. Here, the post‐transcriptional regulatory events governing T‐cell cytokine production are reviewed, with a specific focus on the importance of post‐transcriptional regulation in anti‐tumour responses. Furthermore, potential approaches to circumvent tumour‐mediated dampening of T‐cell effector function through the (dis)engagement of post‐transcriptional events are explored, such as CRISPR/Cas9‐mediated genome editing or chimeric antigen receptors.

Multiple roles for AU-rich RNA binding proteins in the development of haematologic malignancies and their resistance to chemotherapy

“…Increased transcription in activated cells is attributed to the stimulation of transcription factors such as nuclear factor-kappa B (NF-κB), activator protein-1 (AP-1), nuclear factor of activated T cells (NFAT) and CCAAT/enhancer-binding protein β (C/EBPβ). Translation of pro-inflammatory cytokines in leukocytes is regulated by ARE binding proteins [ 105 , 106 ]. The activity of ARE-BPs also determines the stability and decay of inflammation-related transcripts in leukocytes [ 78 , 107 ].…”

nELISA: A high-throughput, high-plex platform enables quantitative profiling of the secretome

“…As seen in Fig 3g, there are 6 examples of a cytokine interaction resulting in a decrease in nELISA protein data, but an increase in CytoSig mRNA data. These interactions involve the expression levels of TNFa, IL-1a, CCL2, and CXCL1, all of which are well-studied examples of cytokines regulated at the level of translation into proteins, as well as mRNA stability [25][26][27][28] . Thus, the nELISA recapitulates well established biology captured by gene expression databases such as CytoSig, in addition to providing protein-level information that is overall a more accurate representation of cell states at the population level.…”

Interaction between gut microbiota and immune checkpoint inhibitor-related colitis

“…Treg cells moderate immunity partly by blocking the induction of IL-2 production in responder T cells and that both IL-10 and TGF-β are engaged in the process ( 75 ). Another mechanism of regulation is cytolysis of target cells mediated by Treg cells, which relies on granzyme A and B in human ( 76 ). Wang et al.…”