Dynamic Post-Transcriptional Events Governing CD8+ T Cell Homeostasis and Effector Function

Abstract

Effective T cell responses against infections and tumors require a swift and ample production of cytokines, chemokines, and cytotoxic molecules. The production of these effector molecules relies on rapid changes of gene expression, determined by cell-intrinsic signals and environmental cues. Here, we review our current understanding of gene-specific regulatory networks that define the magnitude and timing of cytokine production in CD8 + T cells. We discuss the dynamic features of post-transcriptional control during CD8 + T cell homeostasis and activation, and focus on the crosstalk between cell signaling and RNA-binding proteins. Elucidating gene-specific regulatory circuits may help in the future to rectify dysfunctional T cell responses. Regulatory Mechanisms Driving Effective CD8 + T Cell ResponsesCytotoxic CD8 + T cells have a key role in fighting pathogenic insults and in immunosurveillance. This includes clearance of primary infections and killing of malignant cells, as well as long-term protection by memory T cells against secondary infections [1,2]. The effectiveness of CD8 + T cells to clear target cells is defined by their capacity to produce effector molecules, such as cytokines, chemokines, and cytotoxic granule contents. Whereas these effector molecules are essential for killing infected cells and for preventing pathogenic spread, they are also highly toxic. In fact, aberrant cytokine production strongly correlates with the development of autoimmune diseases and inflammatory pathologies, such as rheumatoid arthritis, multiple sclerosis, and various intestinal and skin disorders [3][4][5]. Stringent regulation of inflammatory gene expression is thus key for protective, yet balanced immune responses.Several regulatory nodes define the extent of cytokine production (i.e., protein production) upon T cell activation. Protein production generally initiates with the transcription of DNA into mRNA, a process that depends on the accessibility of genes to, and the availability of, transcription factors. The transcriptional regulatory networks that control mammalian T cell effector functions are well studied and described elsewhere [6,7]. However, the amount of newly transcribed mRNA is not solely defined by transcription rates [8]. Genome-wide studies in bacteria and mammalian cells demonstrated that mRNA and protein abundance do not follow a linear correlation [9][10][11]. For instance, in in vitro activated murine CD4 + T cells, the correlation coefficient is 0.49 [12]. This discordance between mRNA and protein expression has been attributed to several mechanisms of post-transcriptional regulation, including mRNA stability, translation efficiency, and protein degradation.Transcripts encoding effector molecules and regulatory proteins are generally unstable but become stabilized upon T cell activation [13,14]. This increased mRNA stability is required to augment the numbers of transcripts available for protein production and to prolong the immune HighlightsThe rapid remodeling of the T cell proteome upon acti...

Toll‐like receptor‐2/7‐mediated T cell activation: An innate potential to augment CD8+ T cell cytokine production

“…The production of inflammatory cytokines such as IFN‐γ is regulated on multiple levels 57‐62 . Besides the well‐characterized transcriptional and epigenetic regulation that is enforced by transcription factor availability and activation status, as well as histone modification, 57,60,63‐65 post‐transcriptional regulatory events play a crucial role to fine‐tune T cell responses 6,16,62,66‐73 .…”

“…TCR triggering results in the engagement of multiple downstream signalling modules, cooperatively engaging the transcriptional, post‐transcriptional and translational machinery in T cells (Figure 1A). Engagement of the PI3K‐AKT, protein kinase C (PKC) and mitogen‐activated protein kinase (MAPK) pathways result in the initiation of mRNA transcription and can influence cytokine mRNA stability, while activation of mTOR is essential for the initiation of cytokine mRNA translation into protein 6,15,62 . Together, the qualitative and quantitative engagement of these distinct pathways determine the cytokine protein output of T cells upon TCR stimulation 6,62 …”

The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins

“…Their absence in T cells leads to T cell hyperactivation and autoimmune/inflammatory disease. The ZFP36 family of RBP bind AU-rich elements (AREs) present in the 3' untranslated region (3'UTR) of mRNAs and can effect different outcomes promoting RNA decay 19 , suppressing translation 17,20,21 or directing localised translation 22 which are cell-context-specific 23 .…”

The relationship of mRNA with protein expression in CD8+T cells associates with gene class and gene characteristics

“…Evidence is accumulating that in addition to transcriptional and metabolic alterations, posttranscriptional and post-translational mechanisms are critical determinants for T cell effector function (Salerno et al, 2020). In activated Jurkat T cells, for instance, as much as 50% of the transcriptome changes was attributed to alterations in mRNA stability (Cheadle et al, 2005).…”