Dynamic Post-Transcriptional Events Governing CD8+ T Cell Homeostasis and Effector Function
Authors: Fiamma Salerno, Martin Turner, Monika C. Wolkers
Journal: Trends in Immunology (2020)

The rapid remodeling of the T cell proteome upon activation depends on the integration of transcriptional and post-transcriptional control of gene expression.Post-transcriptional events are heterogeneous, dynamic, transcript specific, and cell type specific.RNA-binding proteins mediate post-transcriptional events and their activity is strictly regulated by signal transduction.Post-transcriptional control preserves the silent state of memory T cells, and tailors the magnitude and kinetics of cytokine production in effector T cells.Upon chronic insults, CD8+ T cells can fail to respond, partially because cytokine mRNA is not stabilized and translated. 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. 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. Cytotoxic 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.Harty J.T. et al.CD8+ T cell effector mechanisms in resistance to infection.Annu. Rev. Immunol. 2000; 18: 275-308Crossref PubMed Scopus (480) Google Scholar,2.Masopust D. Schenkel J.M. The integration of T cell migration, differentiation and function.Nat. Rev. Immunol. 2013; 13: 309-320Crossref PubMed Scopus (242) Google Scholar]. 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.Chemin K. et al.Effector functions of CD4+ T cells at the site of local autoimmune inflammation – lessons from rheumatoid arthritis.Front. Immunol. 2019; 10: 353Crossref PubMed Scopus (4) Google Scholar, 4.Das D. et al.Emerging role of immune cell network in autoimmune skin disorders: an update on pemphigus, vitiligo and psoriasis.Cytokine Growth Factor Rev. 2019; 45: 35-44Crossref PubMed Scopus (1) Google Scholar, 5.Killestein J. et al.Cytokine producing CD8+ T cells are correlated to MRI features of tissue destruction in MS.J. Neuroimmunol. 2003; 142: 141-148Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. 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.Chang J.T. et al.Molecular regulation of effector and memory T cell differentiation.Nat. Immunol. 2014; 15: 1104-1115Crossref PubMed Scopus (197) Google Scholar,7.Henning A.N. et al.Epigenetic control of CD8(+) T cell differentiation.Nat. Rev. Immunol. 2018; 18: 340-356Crossref PubMed Scopus (0) Google Scholar]. However, the amount of newly transcribed mRNA is not solely defined by transcription rates [8.Turner M. Is transcription the dominant force during dynamic changes in gene expression?.Adv. Exp. Med. Biol. 2011; 780: 1-13Crossref PubMed Scopus (9) Google Scholar]. Genome-wide studies in bacteria and mammalian cells demonstrated that mRNA and protein abundance do not follow a linear correlation [9.Vogel C. Marcotte E.M. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses.Nat. Rev. Genet. 2012; 13: 227-232Crossref PubMed Scopus (1597) Google Scholar, 10.Maier T. et al.Correlation of mRNA and protein in complex biological samples.FEBS Lett. 2009; 583: 3966-3973Crossref PubMed Scopus (845) Google Scholar, 11.Schwanhausser B. et al.Global quantification of mammalian gene expression control.Nature. 2011; 473: 337-342Crossref PubMed Scopus (2863) Google Scholar]. For instance, in in vitro activated murine CD4+ T cells, the correlation coefficient is 0.49 [12.Tan H. et al.Integrative proteomics and phosphoproteomics profiling reveals dynamic signaling networks and bioenergetics pathways underlying T cell activation.Immunity. 2017; 46: 488-503Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. 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.Anderson P. Post-transcriptional regulons coordinate the initiation and resolution of inflammation.Nat. Rev. Immunol. 2010; 10: 24-35Crossref PubMed Scopus (178) Google Scholar,14.Salerno F. Wolkers M.C. T-cells require post-transcriptional regulation for accurate immune responses.Biochem. Soc. Trans. 2015; 43: 1201-1207Crossref PubMed Scopus (7) Google Scholar]. This increased mRNA stability is required to augment the numbers of transcripts available for protein production and to prolong the immune response [15.Salerno F. et al.Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8(+) T cells.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 9677-9682Crossref PubMed Scopus (7) Google Scholar]. In addition to mRNA stabilization, the protein output is also regulated by its availability for ribosome recruitment (defined, for example, by mRNA localization) and by the efficacy of translation initiation and elongation [13.Anderson P. Post-transcriptional regulons coordinate the initiation and resolution of inflammation.Nat. Rev. Immunol. 2010; 10: 24-35Crossref PubMed Scopus (178) Google Scholar,14.Salerno F. Wolkers M.C. T-cells require post-transcriptional regulation for accurate immune responses.Biochem. Soc. Trans. 2015; 43: 1201-1207Crossref PubMed Scopus (7) Google Scholar,16.Piccirillo C.A. et al.Translational control of immune responses: from transcripts to translatomes.Nat. Immunol. 2014; 15: 503-511Crossref PubMed Scopus (92) Google Scholar]. These post-transcriptional events are mediated by trans-acting factors, such as RNA-binding proteins (RBPs) (see Glossary) and/or non-coding RNAs [microRNAs (miRs) and long non-coding RNAs (lncRNAs)] that recognize specific cis-regulatory elements on target mRNAs [17.Kafasla P. et al.Post-transcriptional coordination of immunological responses by RNA-binding proteins.Nat. Immunol. 2014; 15: 492-502Crossref PubMed Scopus (89) Google Scholar,18.Turner M. et al.Non-coding RNA and its associated proteins as regulatory elements of the immune system.Nat. Immunol. 2014; 15: 484-491Crossref PubMed Scopus (0) Google Scholar]. RBPs and miR can act synergistically or in competition to destabilize mRNA targets and inhibit their translation into proteins (Box 1) [19.Ho J.J. Marsden P.A. Competition and collaboration between RNA-binding proteins and microRNAs.Wiley Interdiscip. Rev. RNA. 2014; 5: 69-86Crossref PubMed Scopus (26) Google Scholar]. The importance of activation-induced alterations in miR expression and activity in T cells has been reviewed elsewhere [20.Ansel K.M. RNA regulation of the immune system.Immunol. Rev. 2013; 253: 5-11Crossref PubMed Scopus (15) Google Scholar]. However, how RBPs mediate post-transcriptional regulatory events in T cells remains largely unexplored. In this review, we discuss recent findings elucidating how RBPs alter their function to govern CD8+ T cell activation and differentiation. We focus on the role of the Zinc finger binding protein 36 (ZFP36) family of RBPs. ZFP36 proteins can block aberrant cytokine production by murine T cells in the absence of stimulation, and can modulate the effector function of T cells upon viral infection [21.Salerno F. et al.Translational repression of pre-formed cytokine-encoding mRNA prevents chronic activation of memory T cells.Nat. Immunol. 2018; 19: 828-837Crossref PubMed Scopus (11) Google Scholar,22.Moore M.J. et al.ZFP36 RNA-binding proteins restrain T cell activation and anti-viral immunity.Elife. 2018; 7e33057Crossref PubMed Scopus (5) Google Scholar]. Based on this example, here we propose a model where RBP-mediated post-transcriptional control instructs CD8+ T cells to respond to antigenic and co-stimulatory signals in a heterogeneous and dynamic fashion.Box 1Cooperation and Competition of miRs and RBPsmiRs and RBPs share the ability to regulate mRNA stability and translation through direct recognition of mRNAs. miRs are important regulators of gene expression during T cell development and effector functions [126.Baumjohann D. Ansel K.M. MicroRNA-mediated regulation of T helper cell differentiation and plasticity.Nat. Rev. Immunol. 2013; 13: 666-678Crossref PubMed Scopus (217) Google Scholar]. In mice, miRNAs generally repress T cell proliferation, differentiation, and cytokine production. Deletion of Dicer, a critical enzyme for miR maturation, impairs the response of murine CD8+ and CD4+ T cells upon in vitro stimulation and in vivo infection with Listeria monocytogenes-OVA [127.Muljo S.A. et al.Aberrant T cell differentiation in the absence of Dicer.J. Exp. Med. 2005; 202: 261-269Crossref PubMed Scopus (472) Google Scholar,128.Zhang N. Bevan M.J. Dicer controls CD8+ T-cell activation, migration, and survival.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 21629-21634Crossref PubMed Scopus (83) Google Scholar]. Let-7 miRs are essential for maintaining the naïve phenotype of murine CD8+ T cells [129.Wells A.C. et al.Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells.Elife. 2017; 6e26398Crossref PubMed Scopus (20) Google Scholar], whereas miR15/16 participate in restricting memory formation [130.Gagnon J.D. et al.miR-15/16 restrain memory T cell differentiation, cell cycle, and survival.Cell Rep. 2019; 28: 2169-2181Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. miR29 suppresses murine CD4+ T cell responses by targeting directly Ifng mRNA, or by targeting mRNA encoding the transcription factors T-bet and Eomes [131.Ma F. et al.The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-gamma.Nat. Immunol. 2011; 12: 861-869Crossref PubMed Scopus (412) Google Scholar,132.Steiner D.F. et al.MicroRNA-29 regulates T-box transcription factors and interferon-gamma production in helper T cells.Immunity. 2011; 35: 169-181Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar]. By contrast, miR155 can promote murine CD8+ T cell responses by inhibiting the antiproliferative effect of type I interferon [133.Gracias D.T. et al.The microRNA miR-155 controls CD8(+) T cell responses by regulating interferon signaling.Nat. Immunol. 2013; 14: 593-602Crossref PubMed Scopus (150) Google Scholar].A critical aspect of post-transcriptional regulation is the crosstalk between different trans-acting factors and the dynamic consequences that these interactions may have on the fate of target mRNAs. miRs and RBPs can cooperate to regulate gene expression, or can exert opposite effects and regulate each other’s function [19.Ho J.J. Marsden P.A. Competition and collaboration between RNA-binding proteins and microRNAs.Wiley Interdiscip. Rev. RNA. 2014; 5: 69-86Crossref PubMed Scopus (26) Google Scholar]. For instance, miR16 and ZFP36 cooperate to accelerate mRNA degradation in HeLa cells. ZFP36 does not directly bind miR16, but interacts with components of the RNA-induced silencing complex (RISC) to assist miR16 in targeting ARE-expressing mRNAs [134.Jing Q. et al.Involvement of microRNA in AU-rich element-mediated mRNA instability.Cell. 2005; 120: 623-634Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar]. Similarly, HuR contributes to recruiting let-7- and miR19-containing RISC to MYC and RHOB target mRNAs, to repress their translation in HeLa cells and human keratinocytes, respectively [135.Kim H.H. et al.HuR recruits let-7/RISC to repress c-Myc expression.Genes Dev. 2009; 23: 1743-1748Crossref PubMed Scopus (361) Google Scholar,136.Glorian V. et al.HuR-dependent loading of miRNA RISC to the mRNA encoding the Ras-related small GTPase RhoB controls its translation during UV-induced apoptosis.Cell Death Differ. 2011; 18: 1692-1701Crossref PubMed Scopus (56) Google Scholar]. RBPs can also directly bind miRs, or compete for overlapping binding sites. For example, Roquin simultaneously interacts with the RISC component Argonaute2, miR146a, and the Icos target mRNA in murine CD4+ T cells, thereby facilitating the decay of both miRs and mRNAs [137.Srivastava M. et al.Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis.Nat. Commun. 2015; 6: 6253Crossref PubMed Scopus (0) Google Scholar]. However, Roquin can also outcompete miR17-92 to bind and regulate Pten mRNA, thus controlling T helper 17, T follicular helper, and T follicular regulatory cell differentiation in mice [138.Essig K. et al.Roquin suppresses the PI3K-mTOR signaling pathway to inhibit T helper cell differentiation and conversion of Treg to Tfr cells.Immunity. 2017; 47: 1067-1082Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. HuR is also known to compete with miRs and to protect target mRNAs from miR-mediated mRNA decay in human and mouse [139.Srikantan S. et al.Functional interplay between RNA-binding protein HuR and microRNAs.Curr. Protein Pept. Sci. 2012; 13: 372-379Crossref PubMed Scopus (106) Google Scholar,140.Bhattacharyya S.N. et al.Relief of microRNA-mediated translational repression in human cells subjected to stress.Cell. 2006; 125: 1111-1124Abstract Full Text Full Text PDF PubMed Scopus (966) Google Scholar]. These few examples show that RBPs can regulate many target mRNAs by using different regulatory strategies. Elucidating the interplay between miRs and RBPs in T cells will contribute to shedding light on the versatility and complexity of post-transcriptional regulatory networks. miRs and RBPs share the ability to regulate mRNA stability and translation through direct recognition of mRNAs. miRs are important regulators of gene expression during T cell development and effector functions [126.Baumjohann D. Ansel K.M. MicroRNA-mediated regulation of T helper cell differentiation and plasticity.Nat. Rev. Immunol. 2013; 13: 666-678Crossref PubMed Scopus (217) Google Scholar]. In mice, miRNAs generally repress T cell proliferation, differentiation, and cytokine production. Deletion of Dicer, a critical enzyme for miR maturation, impairs the response of murine CD8+ and CD4+ T cells upon in vitro stimulation and in vivo infection with Listeria monocytogenes-OVA [127.Muljo S.A. et al.Aberrant T cell differentiation in the absence of Dicer.J. Exp. Med. 2005; 202: 261-269Crossref PubMed Scopus (472) Google Scholar,128.Zhang N. Bevan M.J. Dicer controls CD8+ T-cell activation, migration, and survival.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 21629-21634Crossref PubMed Scopus (83) Google Scholar]. Let-7 miRs are essential for maintaining the naïve phenotype of murine CD8+ T cells [129.Wells A.C. et al.Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells.Elife. 2017; 6e26398Crossref PubMed Scopus (20) Google Scholar], whereas miR15/16 participate in restricting memory formation [130.Gagnon J.D. et al.miR-15/16 restrain memory T cell differentiation, cell cycle, and survival.Cell Rep. 2019; 28: 2169-2181Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. miR29 suppresses murine CD4+ T cell responses by targeting directly Ifng mRNA, or by targeting mRNA encoding the transcription factors T-bet and Eomes [131.Ma F. et al.The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-gamma.Nat. Immunol. 2011; 12: 861-869Crossref PubMed Scopus (412) Google Scholar,132.Steiner D.F. et al.MicroRNA-29 regulates T-box transcription factors and interferon-gamma production in helper T cells.Immunity. 2011; 35: 169-181Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar]. By contrast, miR155 can promote murine CD8+ T cell responses by inhibiting the antiproliferative effect of type I interferon [133.Gracias D.T. et al.The microRNA miR-155 controls CD8(+) T cell responses by regulating interferon signaling.Nat. Immunol. 2013; 14: 593-602Crossref PubMed Scopus (150) Google Scholar]. A critical aspect of post-transcriptional regulation is the crosstalk between different trans-acting factors and the dynamic consequences that these interactions may have on the fate of target mRNAs. miRs and RBPs can cooperate to regulate gene expression, or can exert opposite effects and regulate each other’s function [19.Ho J.J. Marsden P.A. Competition and collaboration between RNA-binding proteins and microRNAs.Wiley Interdiscip. Rev. RNA. 2014; 5: 69-86Crossref PubMed Scopus (26) Google Scholar]. For instance, miR16 and ZFP36 cooperate to accelerate mRNA degradation in HeLa cells. ZFP36 does not directly bind miR16, but interacts with components of the RNA-induced silencing complex (RISC) to assist miR16 in targeting ARE-expressing mRNAs [134.Jing Q. et al.Involvement of microRNA in AU-rich element-mediated mRNA instability.Cell. 2005; 120: 623-634Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar]. Similarly, HuR contributes to recruiting let-7- and miR19-containing RISC to MYC and RHOB target mRNAs, to repress their translation in HeLa cells and human keratinocytes, respectively [135.Kim H.H. et al.HuR recruits let-7/RISC to repress c-Myc expression.Genes Dev. 2009; 23: 1743-1748Crossref PubMed Scopus (361) Google Scholar,136.Glorian V. et al.HuR-dependent loading of miRNA RISC to the mRNA encoding the Ras-related small GTPase RhoB controls its translation during UV-induced apoptosis.Cell Death Differ. 2011; 18: 1692-1701Crossref PubMed Scopus (56) Google Scholar]. RBPs can also directly bind miRs, or compete for overlapping binding sites. For example, Roquin simultaneously interacts with the RISC component Argonaute2, miR146a, and the Icos target mRNA in murine CD4+ T cells, thereby facilitating the decay of both miRs and mRNAs [137.Srivastava M. et al.Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis.Nat. Commun. 2015; 6: 6253Crossref PubMed Scopus (0) Google Scholar]. However, Roquin can also outcompete miR17-92 to bind and regulate Pten mRNA, thus controlling T helper 17, T follicular helper, and T follicular regulatory cell differentiation in mice [138.Essig K. et al.Roquin suppresses the PI3K-mTOR signaling pathway to inhibit T helper cell differentiation and conversion of Treg to Tfr cells.Immunity. 2017; 47: 1067-1082Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. HuR is also known to compete with miRs and to protect target mRNAs from miR-mediated mRNA decay in human and mouse [139.Srikantan S. et al.Functional interplay between RNA-binding protein HuR and microRNAs.Curr. Protein Pept. Sci. 2012; 13: 372-379Crossref PubMed Scopus (106) Google Scholar,140.Bhattacharyya S.N. et al.Relief of microRNA-mediated translational repression in human cells subjected to stress.Cell. 2006; 125: 1111-1124Abstract Full Text Full Text PDF PubMed Scopus (966) Google Scholar]. These few examples show that RBPs can regulate many target mRNAs by using different regulatory strategies. Elucidating the interplay between miRs and RBPs in T cells will contribute to shedding light on the versatility and complexity of post-transcriptional regulatory networks. In mammals, memory CD8+ T cells provide life-long protection against previously encountered pathogens [23.Hammarlund E. et al.Duration of antiviral immunity after smallpox vaccination.Nat. Med. 2003; 9: 1131-1137Crossref PubMed Scopus (579) Google Scholar]. The capacity of memory T cells to produce effector molecules within a few hours of re-infection substantially contributes to preventing pathogen spreading and disease development. Their ‘ready-to-go’ state is empowered by a permissive epigenetic signature, characterized by histone modifications on promoters and distal regulatory elements, which facilitate the accessibility of genes to transcription factors [24.Kaech S.M. et al.Molecular and functional profiling of memory CD8 T cell differentiation.Cell. 2002; 111: 837-851Abstract Full Text Full Text PDF PubMed Scopus (687) Google Scholar, 25.Araki Y. et al.Genome-wide analysis of histone methylation reveals chromatin state-based regulation of gene transcription and function of memory CD8+ T cells.Immunity. 2009; 30: 912-925Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 26.Kakaradov B. et al.Early transcriptional and epigenetic regulation of CD8(+) T cell differentiation revealed by single-cell RNA sequencing.Nat. Immunol. 2017; 18: 422-432Crossref PubMed Scopus (0) Google Scholar]. These epigenetic alterations also allow for the constitutive expression of cytokine mRNAs in both circulating and tissue-resident memory T cells [15.Salerno F. et al.Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8(+) T cells.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 9677-9682Crossref PubMed Scopus (7) Google Scholar,27.Zediak V.P. et al.Cutting edge: persistently open chromatin at effector gene loci in resting memory CD8+ T cells independent of transcriptional status.J. Immunol. 2011; 186: 2705-2709Crossref PubMed Scopus (43) Google Scholar,28.Hombrink P. et al.Programs for the persistence, vigilance and control of human CD8(+) lung-resident memory T cells.Nat. Immunol. 2016; 17: 1467-1478Crossref PubMed Google Scholar]. The ‘pre-arming’ with mRNAs encoding effector molecules is a common determinant of immune cells and enables swift responses to pathogenic insults. In fact, it is also described for natural killer (NK) cells, NKT cells, innate lymphoid cells (ILCs), mast cells, basophils, and eosinophils [29.Stetson D.B. et al.Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function.J. Exp. Med. 2003; 198: 1069-1076Crossref PubMed Scopus (0) Google Scholar, 30.Fehniger T.A. et al.Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs.Immunity. 2007; 26: 798-811Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 31.Gessner A. et al.Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production.J. Immunol. 2005; 174: 1063-1072Crossref PubMed Google Scholar]. However, the constitutive expression of effector mRNAs also poses a health risk. Effector molecules are highly toxic, and aberrant protein production could lead to chronic activation, inflammation, tissue damage, and autoimmune diseases [3.Chemin K. et al.Effector functions of CD4+ T cells at the site of local autoimmune inflammation – lessons from rheumatoid arthritis.Front. Immunol. 2019; 10: 353Crossref PubMed Scopus (4) Google Scholar, 4.Das D. et al.Emerging role of immune cell network in autoimmune skin disorders: an update on pemphigus, vitiligo and psoriasis.Cytokine Growth Factor Rev. 2019; 45: 35-44Crossref PubMed Scopus (1) Google Scholar, 5.Killestein J. et al.Cytokine producing CD8+ T cells are correlated to MRI features of tissue destruction in MS.J. Neuroimmunol. 2003; 142: 141-148Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. It is therefore imperative that protein production from preformed mRNAs should occur primarily upon pathogenic or aberrant cellular insults. To preserve their silent state in the absence of infection, memory T cells tightly regulate the turnover of preformed cytokine mRNA and the initiation of its translation into protein (Figure 1A ) [21.Salerno F. et al.Translational repression of pre-formed cytokine-encoding mRNA prevents chronic activation of memory T cells.Nat. Immunol. 2018; 19: 828-837Crossref PubMed Scopus (11) Google Scholar]. In resting murine CD8+ T cells, the mRNA of effector molecules is generally unstable, and this limits its accumulation [15.Salerno F. et al.Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8(+) T cells.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 9677-9682Crossref PubMed Scopus (7) Google Scholar]. However, rapid mRNA turnover is not sufficient to avoid aberrant protein production. It was recently shown that the translation of preformed mRNA in murine CD44hi-memory-like CD8+ and CD4+ T cells was actively blocked by the RBP ZFP36L2 [21.Salerno F. et al.Translational repression of pre-formed cytokine-encoding mRNA prevents chronic activation of memory T cells.Nat. Immunol. 2018; 19: 828-837Crossref PubMed Scopus (11) Google Scholar]. This process depended on the presence of AU-rich elements (AREs) within the 3′ untranslated region (3′UTR) of Ifng and Tnfa mRNA, and ZFP36L2 directly bound to these AREs in human and mouse T cells [21.Salerno F. et al.Translational repression of pre-formed cytokine-encoding mRNA prevents chronic activation of memory T cells.Nat. Immunol. 2018; 19: 828-837Crossref PubMed Scopus (11) Google Scholar]. The interaction between AREs and ZFP36L2 hampered the recruitment of preformed mRNA to ribosomes, blocked its translation into protein, and prevented aberrant cytokine production in non-activated CD44hi-memory-like CD8+ and CD4+ T cells in mice [21.Salerno F. et al.Translational repression of pre-formed cytokine-encoding mRNA prevents chronic activation of memory T cells.Nat. Immunol. 2018; 19: 828-837Crossref PubMed Scopus (11) Google Scholar]. Moreover, germ-line deletion of the Ifng ARE region [32.Hodge D.L. et al.IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice.J. Autoimmun. 2014; 53: 33-45Crossref PubMed Scopus (37) Google Scholar] has also resulted in chronic IFN-γ production in resting murine NK cells and NKT cells [33.Goedhart M. et al.Interferon-gamma impairs maintenance and alters hematopoietic support of bone marrow mesenchymal stromal cells.Stem Cells Dev. 2018; 27: 579-589Crossref PubMed Scopus (1) Google Scholar], indicating that the ARE-dependent translational block of cytokine production from preformed mRNA also occurs in other immune cells. Of note, a recent study in mice showed that skin-resident Staphylococcus epidermidis-specific CD4+ and CD8+ T cells constitutively expressed a type 2 immunity transcriptome; however, protein production of type 2 cytokines (i.e., IL-5 and IL-13) only occurred upon intradermal injection of chitin or exposure to insect bites [34.Harrison O.J. et al.Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury.Science. 2019; 363eaat6280Crossref PubMed Scopus (0) Google Scholar]. Given that most transcripts encoding inflammatory mediators, including Il5 and Il13, contain AREs in their 3′UTR [35.Vlasova-St Louis I. Bohjanen P.R. Post-transcriptional regulation of cytokine signaling by AU-rich and GU-rich elements.J. Interf. Cytokine Res. 2014; 34: 233-241Crossref PubMed Scopus (0) Google Scholar], it is conceivable that the translational block mediated by ZFP36L2 (or by another ARE-BP) is more broadly applied to block the undesirable release of effector molecules under homeostatic conditions. AREs are not only present in inflammatory genes. They are found in ~16% of the human transcriptome [36.Fallmann J. et al.AREsite2: an enhanced database for the comprehensive investigation of AU/GU/U-rich elements.Nucleic Acids Res. 2016; 44: D90-D95Crossref PubMed Scopus (28) Google Scholar]. New techniques that map RNA–protein interactions genome-wide to a single nucleotide of resolution (Box 2) have revealed that one RBP can interact with a subset of mRNAs sharing specific cis-regulatory elements, such as AREs [37.Galloway A. et al.RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence.Science. 2016; 352: 453-459Crossref PubMed Google Scholar]. In fact, ZFP36L2 does not only bind cytokine mRNAs [21.Salerno F. et al.Translational rep