Cytotoxic T-cells are crucial to protect us from intracellular pathogens and malignant cells. When T-cells become activated, they rapidly secrete cytokines, chemokines and cytotoxic granules that are critical to clear infected cells. However, when not properly regulated, these toxic effector molecules become one of the key mediators of autoimmune diseases. Therefore, a tight and multi-layered regulation of gene expression and protein production is required to ensure a protective yet balanced immune response. In this review, we describe how post-transcriptional events modulate the production of effector molecules in T-cells. In particular, we will focus on the role of cis-regulatory elements within the 3′-UTR of specific mRNAs and on RNA-binding proteins (RBPs) and non-coding RNAs that control the initiation and resolution of T-cell responses.

Introduction

Cytotoxic CD8+ T-cells play an important role in the clearance of viral infections and intracellular pathogens. In addition, memory CD8+ T-cells are generated upon clearance of an infection are maintained in the body to protect us against re-infections. This dual function of T-cells depends on the ample and rapid production of effector molecules, like cytokines, chemokines and cytotoxic granules that arm T-cells to kill infected cells and prevent further spreading of the infection. To do so, T-cells need to receive appropriate activation signals.

When naive CD8+ T-cells encounter the cognate antigen for the first time, they proliferate and differentiate into powerful effector cells that show highly active transcription and rapid maturation of mRNAs to allow for the ample production of effector molecules. Importantly, when the pathogen is cleared, T-cells must rapidly shut down the production of these toxic molecules to prevent damage to the non-infected tissue. Stopping DNA transcription alone however, is not sufficient to immediately halt the immune response, because the mRNA levels may not be immediately affected and protein translation can therefore continue. In addition, many mRNA transcripts encoding for effector molecules, such as RANTES (regulated on activation, normal T-cell expressed and secreted) and interferon (IFN)-γ, remain elevated in memory T-cells when compared with naive T-cells [1,2], whereas their corresponding protein is undetectable. This ‘ready-to-go’ state allows memory T-cells to quickly respond to recurring infections [3], whereas protein production must be prevented in the absence of signals to avoid immunopathology. For this tight control of cytokine production, post-transcriptional regulation is critical. In fact, post-transcriptional events allow T-cells to regulate the intensity and the timing of their immune response by modulating stability, sub-cellular localization and translation of specific mRNA transcripts. Table 1 gives an overview of currently known cytotoxic T-cell-related genes that are post-transcriptionally regulated in T-cells or in other immune cell types.

Table 1
Cytotoxic T-cell-related genes that can be regulated at post-transcriptional level

Abbreviations: AUF-1, AU-rich element RNA-binding protein 1; CXCL, chemokine (C-X-C motif) ligand; EPRS, glutamyl-prolyltRNAsynthetase; IP-10, interferon gamma-induced protein 10; JNK, c-Jun N-terminal kinases; MRE, miR recognition elements; TIAR, T-cell restricted antigen-related protein; YB-1, Y box binding protein 1.

mRNA cis-elements within 5′-UTR cis-elements within 3′-UTR trans-elements mechanisms of control references 
CCL3 n.d. ARE TTP mRNA stability [50
CCL5 (RANTES) n.d. stem-loop structure n.d. mRNA stability, translational block [2,51
CCL11 (Eotaxin) n.d. ARE HuR mRNA stability [52
CCL22 n.d. GAIT EPRS Translational block [42
COX-2 n.d. ARE TTP, HuR, TIA-1, TIAR, CUGB2, miR-16 mRNA stability [39,41,5355
CXCL10 (IP-10) n.d. n.d. n.d. mRNA stability [56,57
Fas ligand n.d. ARE, MRE HuR, miR-21 mRNA stability [58,59
GM-CSF  ARE TTP, AUF1 mRNA stability, translational block [25,6062
Granzyme B n.d. n.d. n.d. Translational block [63
IFN-γ pseudoknot structure ARE, MRE TTP, HuR, miR-29 mRNA stability, translational block [14,24,35,64
IL-2 JNK response elements ARE, MRE Nucleolin, YB-1, TTP, NF-90, miR-181c mRNA stability, translational block [13,23,6567
IL-3 n.d. ARE TTP mRNA stability [68,69
IL-6 n.d. ARE, MRE, stem-loop structure TTP, AUF-1 mRNA stability [70,71
IL-11 n.d. ARE, GRE CUGBP1 mRNA stability [72
IL-15 aberrant AUG starting codon n.d. n.d. Translational block [73,74
IL-18 n.d. n.d. n.d. mRNA stability [75
Perforin n.d. MRE miR-139 Translational block [37
TNF-α n.d. ARE, CDE, MRE TTP, HuR, TIA-1, TIAR, Roquin, miR-16, miR-221 mRNA stability, translational block [14,25,31,38,39,41
mRNA cis-elements within 5′-UTR cis-elements within 3′-UTR trans-elements mechanisms of control references 
CCL3 n.d. ARE TTP mRNA stability [50
CCL5 (RANTES) n.d. stem-loop structure n.d. mRNA stability, translational block [2,51
CCL11 (Eotaxin) n.d. ARE HuR mRNA stability [52
CCL22 n.d. GAIT EPRS Translational block [42
COX-2 n.d. ARE TTP, HuR, TIA-1, TIAR, CUGB2, miR-16 mRNA stability [39,41,5355
CXCL10 (IP-10) n.d. n.d. n.d. mRNA stability [56,57
Fas ligand n.d. ARE, MRE HuR, miR-21 mRNA stability [58,59
GM-CSF  ARE TTP, AUF1 mRNA stability, translational block [25,6062
Granzyme B n.d. n.d. n.d. Translational block [63
IFN-γ pseudoknot structure ARE, MRE TTP, HuR, miR-29 mRNA stability, translational block [14,24,35,64
IL-2 JNK response elements ARE, MRE Nucleolin, YB-1, TTP, NF-90, miR-181c mRNA stability, translational block [13,23,6567
IL-3 n.d. ARE TTP mRNA stability [68,69
IL-6 n.d. ARE, MRE, stem-loop structure TTP, AUF-1 mRNA stability [70,71
IL-11 n.d. ARE, GRE CUGBP1 mRNA stability [72
IL-15 aberrant AUG starting codon n.d. n.d. Translational block [73,74
IL-18 n.d. n.d. n.d. mRNA stability [75
Perforin n.d. MRE miR-139 Translational block [37
TNF-α n.d. ARE, CDE, MRE TTP, HuR, TIA-1, TIAR, Roquin, miR-16, miR-221 mRNA stability, translational block [14,25,31,38,39,41

The fate of cytokine mRNA depends on both flavour and intensity of activation signals that T-cells receive. These signals determine the decoration of mRNAs with RNA-binding proteins (RBPs) and/or antisense RNAs, such as micro-RNA (miRs) and long non-coding RNA (lncRNAs) on the 5′- and 3′-UTRs and possibly on the coding region.

The 3′-UTR is a potent regulator of mRNA stability and translation [4] and, as recently discovered, of membrane protein localization [5]. Evolutionary studies have shown that its length is directly correlated with the expansion of post-transcriptional regulatory circuits and the morphological complexity of different metazoan species [6]. In cytokine mRNAs, the length of the 3′-UTR often exceeds that of the coding sequence [7], suggesting that it plays a critical role to determine mRNA fate. In addition, polymorphisms in the 3′-UTR of immune related mRNAs, like tumour necrosis factor (TNF)-α [8], interleukin (IL)-6 [9] and the T-cell receptor (TCR) ζ chain [10], can induce autoimmunity by disrupting the balance between mRNA stability and decay.

3′-UTR-dependent post-transcriptional events are determined by cis-regulatory elements that consist of nt sequences, secondary structures or a combination of the two. One of these sequences, adenylate uridylate (AU)-rich elements (AREs), is found in ∼16% of human protein-coding genes [11] including many cytokines and inflammatory genes (Table 1). AREs are potent cis-acting determinants of mRNA turnover and translation. Here we discuss how ARE-dependent and ARE-independent post-transcriptional events governed by the 3′-UTR modulate T-cell effector function and how the regulation alters during the course of a T-cell response.

Post-transcriptional events promote T-cell effector functions

Many cytokine and chemokine-encoding transcripts are intrinsically unstable when T-cells are not activated. However, T-cell triggering through the TCR, together with co-stimulatory signals, leads to rapid mRNA stabilization (Figure 1, left). For instance, mRNA of the key cytokines IL-2, IFN-γ, TNF-α and granulocyte-macrophage colony-stimulating factor (GM-CSF) are stabilized when the co-stimulatory molecules CD28 (cluster of differentiation 28) and lymphocyte function-associated antigen 1 (LFA-1) are engaged [1214]. Interestingly, stabilization of these transcripts is primarily driven by the recognition of AREs within the 3′-UTR by RBPs such as nuclear factor 90 (NF-90, for IL-2) and ELAV-like protein 1 or human antigen R (HuR, for TNF-α and IFN-γ) [13,14]. Both RBPs employ a similar mode of action: post-translational modification upon T-cell activation of NF90 and HuR leads to translocation from the nucleus to the cytoplasm where they bind to ARE-containing transcripts. How ARE-binding proteins (ARE-BPs) stabilize these intrinsically unstable mRNAs in T-cells is still not fully understood. Studies on lipopolysaccharide-stimulated macrophages describe a phosphorylation-regulated exchange of mRNA decay-inducing tristetraprolin (TTP) with the stabilizing ARE-BP HuR, thereby promoting translation [15]. Alternatively, studies in human embryonic kidney (HEK)293T cells propose that HuR redirects the mRNA to polysomes for active translation by oligomerizing along the RNA and cause the dissociation of miRs from the target mRNA [16] (Figure 1, left).

Post-transcriptional regulatory mechanisms during T-cell responses

Figure 1
Post-transcriptional regulatory mechanisms during T-cell responses

Activation: (1) T-cells become activated by TCR triggering in combination with co-stimulatory molecules like CD28 and LFA-1. (2) Transcription of effector molecules is rapidly initiated. When the mature mRNA is translocated into the cytoplasm, (3) stabilizing RBPs like HuR or NF-90 can bind ARE-bearing transcripts and replace destabilizing ARE-BPs or act as scaffold and mask miR-binding sites. The eIF4F complex (including eIF4E protein) binds to the mRNA and translation commences. (4) Activated T cells maintain effector function by a global down-regulation of miR expression. (5) Alternatively, circular lncRNAs may act as a sponge for miRs, or (6) recruit complementary miRs to induce their degradation. Downregulation: When the pathogen is cleared (1) the antigens are still present and TCR triggering may still occur. (2) Therefore, transcription of genes encoding effector molecule can carry on. (3) Cytoplasmic mRNA deadenylation and degradation can be promoted by destabilizing RBPs that recognize AREs or CDEs or by miRs binding to miR recognition elements (MREs). In this late effector phase of T-cells, mRNA can still be recognized by the eIF4F complex and translated into protein if needed. (4) miR expression levels increase again Memory: (1) In the absence of TCR triggering, (2) memory T-cells maintain an open chromatin structure and continuously generate mRNA transcripts encoding for specific effector molecules. (3) Protein production is hampered by a translational block, possibly mediated by e.g. GAIT elements or AREs, together with active mRNA degradation. Furthermore, the eIF4E protein is recruited by eIF4E-BP and the translational initiation complex cannot be formed. (4) miR levels are maintained at high levels.

Figure 1
Post-transcriptional regulatory mechanisms during T-cell responses

Activation: (1) T-cells become activated by TCR triggering in combination with co-stimulatory molecules like CD28 and LFA-1. (2) Transcription of effector molecules is rapidly initiated. When the mature mRNA is translocated into the cytoplasm, (3) stabilizing RBPs like HuR or NF-90 can bind ARE-bearing transcripts and replace destabilizing ARE-BPs or act as scaffold and mask miR-binding sites. The eIF4F complex (including eIF4E protein) binds to the mRNA and translation commences. (4) Activated T cells maintain effector function by a global down-regulation of miR expression. (5) Alternatively, circular lncRNAs may act as a sponge for miRs, or (6) recruit complementary miRs to induce their degradation. Downregulation: When the pathogen is cleared (1) the antigens are still present and TCR triggering may still occur. (2) Therefore, transcription of genes encoding effector molecule can carry on. (3) Cytoplasmic mRNA deadenylation and degradation can be promoted by destabilizing RBPs that recognize AREs or CDEs or by miRs binding to miR recognition elements (MREs). In this late effector phase of T-cells, mRNA can still be recognized by the eIF4F complex and translated into protein if needed. (4) miR expression levels increase again Memory: (1) In the absence of TCR triggering, (2) memory T-cells maintain an open chromatin structure and continuously generate mRNA transcripts encoding for specific effector molecules. (3) Protein production is hampered by a translational block, possibly mediated by e.g. GAIT elements or AREs, together with active mRNA degradation. Furthermore, the eIF4E protein is recruited by eIF4E-BP and the translational initiation complex cannot be formed. (4) miR levels are maintained at high levels.

Non-coding RNAs also play a critical role in the regulation of effector function. For instance, a global repression of miRs is observed in effector T-cells compared with naive T-cells (Figure 1, left) [17]. In addition, several transcripts employ alternative poly-adenylation sites upon T-cell activation to generate shorter 3′-UTRs, which results in the loss of specific miR-binding sites and hence protect target mRNAs from degradation [18]. Furthermore, genome-wide analysis showed that CD8+ T-cells express hundreds of lncRNAs upon antigen recognition [19]. Although their specific function has not been identified yet, lncRNAs could possibly support T-cell function by acting as a ‘sponge’ for miRs or by promoting degradation of miRs with complementary sequences [20,21] (Figure 1, left).

In summary, a powerful inflammatory response requires the stabilization of cytokine mRNA and the support of co-stimulatory molecules is essential herein. However, how the strength of signals determines the fate of mRNA in T-cells is not yet known. In particular, memory T-cells respond more rapidly and to much lower antigen levels compared with naive T-cells. Intriguingly, they can also respond to infections in an antigen-independent fashion, triggered by cytokines [22] and possibly by other inflammatory signals. Whether cytokine production requires mRNA stabilization per se or whether sub-optimal T-cell activation also allows direct translation of unstable mRNA remains an open question.

RBPs and non-coding RNAs turn off T-cell responses

Once the infection is resolved, cytokine production must be rapidly terminated. To achieve this, again post-transcriptional events controlled by RBPs and/or miRs are indispensable (Figure 1, middle). For instance, TTP binds to ARE-bearing transcripts and induces the degradation of IFN-γ and IL-2 mRNA in T-cells [23,24] and of TNF-α and GM-CSF mRNA in primary bone marrow stromal cells and macrophages [25]. Mice lacking TTP develop a complex inflammatory syndrome that is associated with a prolonged TNF-α mRNA half-life and elevated levels of circulating TNF-α [26]. Likewise, deletion of AREs within the 3′-UTR of TNF-α and IFN-γ results in chronic protein production that causes spontaneous development of chronic inflammatory arthritis, Crohn's-like inflammatory bowel disease, Lupus-like disease and aplastic anaemia [2729].

More cis-regulatory elements targeted by RBPs for mRNA degradation have been identified in 3′-UTRs. GU-rich elements (GREs) are recognized by the CUG-binding protein 1 (CUGBP1) and are highly expressed in short-lived transcripts mediating intracellular signalling cascades in T-cells, such as myeloid differentiation primary response gene 88 (MyD88), protein kinase B (PKB or Akt) and transcription factor jun-B [30]. Constitutive decay elements (CDE) form conserved secondary structures and are hubs for RBPs like Roquin, promoting e.g. ICOS (inducible T-cell costimulator) and TNF-α mRNA degradation in T-cells and macrophages, respectively [3133].

Also miRs are critical for mRNA degradation during the shut-down of T-cell responses. In fact, during the resolution of an infection, their expression levels rise back to original levels [17] (Figure 1, middle). The role of miRs in regulating T-cell responses is further emphasized by the knockout of the miR-processing enzyme Dicer in CD8+ T-cells that enhanced T-cell activation [34]. Other landmark studies have identified specific miRs for cytokine degradation. miR-29 reduces IFN-γ mRNA levels by directly binding to IFN-γ mRNA [35] or by targeting two critical transcription factors for IFN-γ, the T-box transcription factors T-bet and eomesodermin [36]. miR-139 represses the expression of perforin and eomesodermin and miR-150 reduces IL-2 receptor α-chain (CD25) expression in CD8+ T-cells [37]. Interestingly, TNF-α mRNA degradation in macrophages and HeLa cells depends on the co-operation between TTP and miR-221 or miR-16 [38,39]. TTP does not directly bind to miRs, but associates with the RNA-induced silencing (RISC) complex, which in turn stabilizes the interaction of miRs loaded in the RISC complex with the target mRNA to accelerate degradation. These latter studies are one of the few studies thus far demonstrating the interplay of different regulatory mechanisms, whereas this co-operation is possibly rather the rule than the exception.

What keeps memory T-cells quiescent?

Whereas there is a solid set of data on mRNA decay in T-cells, much less is known about the regulation of translation. This process has been proposed to keep self-reactive T-cells anergic [40] and it may also be important to prevent excessive production of cytokines during the effector phase. Unpublished work from our laboratory shows that mRNA degradation together with blocking translation of preformed RNA is crucial to keep cytokine gene expression in memory T-cells in check (Figure 1, right).

RBPs modulating translational processes have been primarily studied in activated macrophages. For instance, HuR overexpression does not alter the mRNA levels of TNF-α and cyclooxygenase-2 (COX-2), but recruits the translational silencer TIA-1 (T-cell intracellular antigen 1) onto the mRNA [41]. TIA-1 binding to AREs diverts the target RNAs from polysomes to untranslated messenger ribonucleoproteins (mRNPs) to block mRNA translation and dampen the inflammatory response. In addition, exposure of macrophages to IFN-γ engages the IFN-γ activated inhibitor of translation (GAIT) complex, a heterotetramer that binds to conserved stem-loop secondary structures in the 3′-UTR of e.g. chemokine (C-C motif) ligand 22 (CCL22) [42] and ceruloplasmin [43]. This interaction hampers the entry of the translational pre-initiation complex at the 5′-UTR of target mRNAs.

Interestingly, non-coding RNAs can also contribute to translational inhibition. Whereas perfect base-pairing of miRs with their target mRNA supports mRNA degradation, imperfect complementarity primarily results in translational inhibition [44]. In zebrafish [45], Drosophila S2 cells [46] and HeLa cells [47], miRs were shown to repress the translation of newly synthesized mRNAs without affecting the mRNA levels. Those findings may be explained by affecting translation itself or, alternatively, by mRNA deadenylation, which may lead to decreased translation efficiency [48]. Also lncRNAs can inhibit mRNA translation in HeLa cells [49]. lncRNA–p21 interacts with polysomes and inhibits mRNA translation by interfering with the binding of the eukaryotic translation initiation factor 4E (eIF4E) on the mRNA. lncRNA-p21 levels rise when HuR levels are low, thereby this mechanism does not occur when HuR levels are high [49]. Whereas some of the processes blocking translation will also apply to T-cells, cell-type-specific regulation may occur, which should be further investigated.

Conclusions and prospective

In this review, we summarized our current knowledge of post-transcriptional events in T-cells. Dysfunctional post-transcriptional regulation leads to immunopathology and autoimmune diseases, but also possibly to non-functional T-cells in cancer. Therefore, a detailed understanding on how T-cells fine-tune the production of effector molecules will be instrumental to develop new T-cell therapies. We believe that selective manipulation of these events could in fact rectify aberrant T-cell function.

To date however, most studies analysed single aspects of post-transcriptional regulation, offering only a limited picture of the greater complexity of post-transcriptional regulatory networks. Different ribonucleoprotein complexes in fact may compete for common binding sites, as is the case of AREs, or bind to distinct non-overlapping sites and complement each other's function. This is, for instance conceivable, for mRNAs containing many cis-regulatory elements within their 3′-UTR, such as TNF-α. Furthermore, although in vitro studies employing cell lines and bulk cell populations were fundamental for our understanding of post-transcriptional mechanisms, the kinetics of an in vivo T-cell response is substantially lost. Whether post-transcriptional events change during an infection and how they are maintained in memory T-cells, is therefore still unknown. The use of new techniques such as RNA-fluorescent in situ hybridization (RNA–FISH), RNA–protein pull-down in primary T-cells and in vivo silencing of specific regulatory trans-elements in T-cells will unravel post-transcriptional regulatory networks during different stages of T-cell activation. Although technically challenging, single cell analysis should provide profound insights in the dynamics of T-cell responses.

Funding

This work was supported by the Sanquin Blood Supply Foundation and the Dutch Science Foundation [grant number 917.14.214 (to M.C.W.)].

Abbreviations

     
  • ARE

    AU-rich element

  •  
  • ARE-BP

    ARE-binding protein

  •  
  • AU

    adenylate uridylate

  •  
  • CCL

    chemokine (C-C motif) ligand

  •  
  • CDE

    constitutive decay elements

  •  
  • CUGBP1

    CUG-binding protein 1

  •  
  • GAIT

    IFN-γ activated inhibitor of translation

  •  
  • GRE

    GU-rich elements

  •  
  • HuR

    human antigen R

  •  
  • IFN

    interferon

  •  
  • IL

    interleukin

  •  
  • lncRNA

    long non-coding RNA

  •  
  • miR

    miRNA

  •  
  • NF-90

    nuclear factor 90

  •  
  • RBP

    RNA-binding protein

  •  
  • TCR

    T-cell receptor

  •  
  • TIA-1

    T-cell intracellular antigen 1

  •  
  • TNF

    tumour necrosis factor

  •  
  • TTP

    tristetraprolin

Translation UK 2015: Held at the University of Aberdeen, U.K., 7–9 July 2015.

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