IRF4 Provides Rations for Cytotoxic CD8+ T Cell Soldiers

View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Immunity Previews IRF4 Provides Rations for Cytotoxic CD8+ T Cell Soldiers Magdalena Huber1 and Michael Lohoff1,* 1Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, 35043 Marburg, Germany *Correspondence: [email protected] http://dx.doi.org/10.1016/j.immuni.2013.10.008 The transcription factor IRF4 is known to be essential for differentiation of effector CD4+ T cell subsets. In this issue, Yao et al. (2013) identify IRF4 as a regulator of checkpoints in the final steps and maintenance of CD8+ T cell effector differentiation. The transcription factor IRF4 belongs to beyond normal text book knowledge and this correlated with elevated activity the family of interferon regulatory factors became obvious, because IRF4-sufficient of mTOR; conversely, inhibition of the (IRFs) consisting of nine members in Tc17 cells provided ‘‘reverse help’’ via mTOR pathway caused downregulation mice and humans that play important roles cell-associated IL-17A to CD4+ T cells for of IRF4. Because IRF4 expression has in the regulation of innate and adaptive im- Th17-cell-mediated encephalomyelitis. been shown to depend on interleukin-2 mune responses as well as in oncogenesis Three parallel papers from Yao et al. (IL-2)-inducible T cell kinase (ITK), the au- (Biswas et al., 2010). IRF4 has long been (2013) (in this issue of Immunity), our thors used inhibitors for both ITK and known to be essential for differentiation own group (Raczkowski et al., 2013), mTOR and demonstrated that these two of the effector CD4+ T helper cell subsets and the group of Kallies (Man et al., signaling pathways seemed to cooperate Th2, Th9, Th17, and Tfh (Biswas et al., 2013) now describe that IRF4 is also for IRF4 induction. The relevance of IRF4 2010; Bollig et al., 2012; Bru¨ stle et al., crucial for the sustained expansion and for CD8+ T cell function was studied in 2007; Staudt et al., 2010). This IRF4 effector function of cytotoxic CD8+ mice with conditional deletion of IRF4 in dependence is reflected by the total resis- T lymphocytes. It is current knowledge CD8+ T cells. The genetic ablation strategy tance of IRF4-deficient mice to diseases in that upon infection with intracellular caused IRF4 deletion mostly in mature which these cells are pathogenic such as pathogens, specific CD8+ T cells become CD8+ T cells and had no relevant influence allergic asthma, experimental allergic activated in peripheral lymphatic organs, on CD4+ T cells. In this system, IRF4 encephalomyelitis (EAE), and inflamma- proliferate, and differentiate into CTLs. expression in CD8+ T cells was important tory bowel disease. Along these lines, it Upon antigen encounter in peripheral tis- for clearance of influenza infection as has been shown that IRF4 cooperates sue, these effector CD8+ T cells produce well as for recovery from disease. As with BATF-JUN transcription factor heter- inflammatory cytokines and are endowed compared to WT counterparts, IRF4-defi- odimers for binding to AP-1-IRF4 com- with the property to kill infected cells. cient CTLs proliferated less, were more posite elements (AICE), as reviewed in After resolution of infection, the bulk of prone to apoptosis, and produced fewer detail in Murphy et al. (2013). Upon bind- CTLs dies; however, a small fraction effector molecules crucial for viral clear- ing, chromatin modifications occur that persists as long-lived memory cells that ance such as Granzyme B and inter- allow in a second step the access of the respond with strong proliferation and feron-g (IFN-g). Complementary to these Th17-cell-specific transcription factor rapid reconversion into effectors upon data, our group has shown in another in- RORgt. Possibly, similar modifications re-exposure to the cognate pathogen. fectious model that IRF4-deficient mice also permit binding of other subset- The phenotypic and functional changes cannot clear the intracellular bacterial specific transcription factors like GATA-3 toward effector and memory differentia- pathogen Listeria monocytogenes, also in the respective Th cell subsets. tion are regulated by gradual expression because of intrinsic defects in CD8+ Earlier this year, it was described that of several transcription factors. Whereas T cell expansion and effector function IRF4 is also required for the development Bcl6, Eomes, Id3, and TCF1 are associ- (Raczkowski et al., 2013). Lack of main- of IL-17-producing CD8+ T (Tc17) cells ated with memory cell differentiation and tained CD8+ T cell effector function in the (Huber et al., 2013). In this context, longevity of cells, T-bet, Id2, and Blimp-1 absence of IRF4 is also demonstrated in IRF4 regulated Tc17 differentiation by promote effector cell development (Kaech the third mentioned study (Man et al., increasing the amounts of transcription and Cui, 2012). 2013). factors crucial for type 17 helper cell By using low- and high-affinity peptides, To gain mechanistic insights into how differentiation (RORgt and RORa)on Yao et al. (2013) elegantly demonstrate IRF4 regulates antiviral CD8+ T cell one hand and by decreasing transcription that IRF4 expression in CD8+ T cells criti- immune responses, Yao et al. (2013) factors regulating alternative fates, like cally depended on the strength of the cocultured CD8+ T cells and dendritic cells regulatory T (Treg)-cell-specific Foxp3 T cell receptor (TCR)-ligand interaction in vitro. Similar to us, they found that early and cytotoxic T lymphocyte (CTL)-spe- and on mammalian target of rapamycin after activation, IRF4-deficient CD8+ cific eomesodermin (Eomes), on the other. (mTOR) activity. Thus, strong TCR T cells expanded and displayed normal Importantly, a function of CD8+ T cells signaling induced high IRF4 expression expression of the activation markers Immunity 39, November 14, 2013 ª2013 Elsevier Inc. 797 Immunity Previews Yao et al. (2013). When comparing the Nonproductively phenotype of BATF- and IRF4-deficient + + activated CD8 T cell Effector CD8 T cell CD8+ T cells, these authors found that IRF4 and BATF defects overlapped only IRF4lo IRF4hi partially. Obviously, survival of CD8+ lo hi Blimp-1 Strength of Blimp-1 T cells is cooperatively regulated by both Low glycolysis TCR ligation High glycolysis + + mTOR activity + ++ IRF4 and BATF, whereas in contrast the CD44 CD25 CD44 CD25 + GzmBlo IFN- hi IRF4 expression GzmBhi IFN- hi expansion of CD8 T cells seems to be mediated by IRF4 in a BATF-independent Activation Proliferation Differentiation manner. Taken together, the three recently published reports consistently show Chronic infection Pathogen clearance that expression of IRF4 in CTLs depends on the strength of TCR ligation. Although Figure 1. Relationship between Strength of TCR Ligation, IRF4 Expression, and the dispensable for early activation events as Development of Effector CD8+ T Cells measured by phenotypical changes, pro- Strong TCR ligation causes increased mTOR activity, high expression of IRF4 and Blimp-1, and highly liferation, and cytokine production, IRF4 active aerobic glycolysis in CD8+ T cells. IRF4 enables maintained expansion and differentiation into effector CD8+ T cells characterized by high expression of the surface markers CD44 and CD25 and is essential for the maintenance of CTL the effector molecules GzmB and IFN-g. These effector cells efficiently clear infections with intracellular properties and thus for establishment pathogens. In contrast, suboptimal TCR signaling causes lower mTOR activity and low IRF4 as well as of a fully functional effector and also Blimp-1 expression. Such nonproductively activated CD8+ T cells still express CD44 and CD25 but perform only limited glycolysis and fail to maintain proliferation and differentiation into effector cells. memory pool. IRF4 seems to regulate These cells express GzmB and IFN-g at low amounts, fail to clear pathogens, and enable development these functions at several levels, acting of chronic infection. as both transcriptional repressor and activator. The three studies agree that CD69 and CD25, as well as of the effector Blimp1, T-bet, and HIF1a. Furthermore, the direct positive regulation of Prdm1 molecules IFN-g and Granzyme B. How- IRF4 mediated histone modification and gene expression contributes to the IRF4 ever, maintenance of proliferation was alteration of T-bet binding to the pro- effects. The study by Yao et al. (2013) severely hampered, effector differentia- moters of the effector molecules Gzmb includes the regulation of cyclin-kinase tion failed to proceed, and cell death was and Ifng. As for the effects on the Blimp-1 inhibitors, antiapoptotic molecules, and enhanced. All these defects were rescued protein encoded by Prdm1, they were also T-bet and chromatin modifications to by overexpression of IRF4, which ex- reported by Raczkowski et al. (2013) and the spectrum of IRF4 targets in differen- cludes developmental alterations of are reminiscent to similar functions of tiating effector CD8+ T cells. The study IRF4-deficient CD8+ T cells prior to IRF4 in B and CD4+ T cells. Moreover, by Man et al. (2013) suggests an impor- effector cell differentiation. When IRF4 seems to support CD8+ T cell tant role of IRF4 in the regulation of analyzing the molecular mechanisms effector differentiation also by controlling cellular metabolic pathways. Thus, IRF4 of how IRF4 sustains the expansion of glucose metabolism and glycolysis via has central basic functions and also CD8+ T cells, Yao et al. (2013) found that the HIF complex. This is the result of the context-dependent functions, such as IRF4 repressed several cyclin-dependent third mentioned study (Man et al., 2013), during T cell subset differentiation (e.g., kinase inhibitors (such as Cdkn2a, which elegantly identifies roles of IRF4 Tc17 and Th17), which may be regulated Cdkn1a, and Cdkn1c) and directly bound not only on Hif1a and Foxo1, transcription by diverse cooperating transcription fac- to the Cdkn2a locus. As for CD8+ T cell factors regulating metabolic pathways, tors.

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