Transcription Factor IRF4 Promotes CD8 T Cell Exhaustion and Limits
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Article Transcription Factor IRF4 Promotes CD8+ T Cell Exhaustion and Limits the Development of Memory- like T Cells during Chronic Infection Graphical Abstract Authors Kevin Man, Sarah S. Gabriel, Yang Liao, ..., Mark A. Febbraio, Wei Shi, Axel Kallies Correspondence [email protected] In Brief During chronic stimulation, CD8+ T cells acquire an exhausted phenotype characterized by expression of inhibitory receptors, loss of effector function, and metabolic impairments. Man et al. have identified a transcriptional module consisting of the TCR-induced transcription factors IRF4, BATF, and NFATc1 that drives T cell exhaustion and impairs memory T cell development. Highlights d High IRF4 mediates T cell exhaustion including expression of inhibitory receptors d TCR-responsive transcription factors IRF4, BATF, and NFAT form a transcriptional circuit d Low IRF4 reduces T cell exhaustion and promotes formation of TCF1+ memory-like T cells Man et al., 2017, Immunity 47, 1129–1141 December 19, 2017 Crown Copyright ª 2017 Published by Elsevier Inc. https://doi.org/10.1016/j.immuni.2017.11.021 Immunity Article Transcription Factor IRF4 Promotes CD8+ TCell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection Kevin Man,1,2,10,11 Sarah S. Gabriel,1,8,9,10 Yang Liao,1,2 Renee Gloury,1,8,9 Simon Preston,1,2 Darren C. Henstridge,3 Marc Pellegrini,1,2 Dietmar Zehn,4 Friederike Berberich-Siebelt,5,6 Mark A. Febbraio,7 Wei Shi,1,2 and Axel Kallies1,8,9,12,* 1The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia 2The Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia 3Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia 4Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany 5Institute of Pathology, University of Wurzburg,€ 97080 Wurzburg,€ Germany 6Comprehensive Cancer Center Mainfranken, University of Wurzburg,€ 97080 Wurzburg,€ Germany 7Cellular and Molecular Metabolism, Garvan Institute, Sydney, NSW 2010, Australia 8Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC 3010, Australia 9The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia 10These authors contributed equally 11Present address: Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA 12Lead Author *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2017.11.021 SUMMARY that is defined by the progressive loss of effector function and impaired memory T cell potential (Virgin et al., 2009; Speiser During chronic stimulation, CD8+ T cells acquire an et al., 2014; Kahan et al., 2015; Wherry and Kurachi, 2015). exhausted phenotype characterized by expression Exhausted T cells successively lose their ability to produce of inhibitory receptors, down-modulation of effector cytokines, including interferon-gamma (IFN-g), tumor necrosis function, and metabolic impairments. T cell exhaus- factor (TNF), and interleukin-2 (IL-2), and exhibit impaired tion protects from excessive immunopathology but survival, eventually leading to the deletion of antigen-specific limits clearance of virus-infected or tumor cells. We cells. They express multiple inhibitory receptors, including programmed cell-death 1 (PD-1), lymphocyte-activation gene transcriptionally profiled antigen-specific T cells 3 (Lag3), TIM-3, CTLA4, TIGIT, and 2B4, associated with func- from mice infected with lymphocytic choriomeningi- tional impairments. Conversely, inhibitory receptors are required tis virus strains that cause acute or chronic disease. to prevent overt immune pathology due to chronic stimulation of T cell exhaustion during chronic infection was driven antigen-specific T cells (Blackburn et al., 2009; Virgin et al., 2009; by high amounts of T cell receptor (TCR)-induced Speiser et al., 2014; Kahan et al., 2015; Wherry and Kurachi, transcription factors IRF4, BATF, and NFATc1. 2015). For example, PD-1 binding to either PD ligand (PD-L)1 These regulators promoted expression of inhibitory or PD-L2 facilitates the dephosphorylation of key proteins receptors, including PD-1, and mediated impaired downstream of the T cell receptor (TCR), leading to the inhibition cellular metabolism. Furthermore, they repressed of TCR-dependent signal transduction (Keir et al., 2008). T cell the expression of TCF1, a transcription factor exhaustion has recently been linked to defects in cellular meta- required for memory T cell differentiation. Reducing bolism (Gubin et al., 2014; Staron et al., 2014; Bengsch et al., 2016; Schurich et al., 2016), which has emerged as a major IRF4 expression restored the functional and checkpoint in adaptive immune responses (Pearce et al., 2013; metabolic properties of antigen-specific T cells and Wang and Green, 2012). Indeed, compromised metabolic promoted memory-like T cell development. These fitness is closely linked to the functional impairments of tumor- findings indicate that IRF4 functions as a central infiltrating T cells that frequently display an exhausted phenotype node in a TCR-responsive transcriptional circuit (Chang et al., 2015; Ho et al., 2015). Recently, PD-1 signaling that establishes and sustains T cell exhaustion was shown to directly contribute to establishing the metabolic during chronic infection. impairments of exhausted T cells (Bengsch et al., 2016), suggesting that exhaustion is underpinned by substantial rewiring of TCR signaling-mediated metabolic processes. INTRODUCTION Several studies have demonstrated that exhausted T cells are characterized by a transcriptional program that is distinct from T cells responding to persistent viral or tumor antigens acquire effector and memory T cells that arise during acute infection an altered state of differentiation referred to as ‘‘exhaustion’’ (Wherry et al., 2007; Doering et al., 2012; Kahan et al., 2015). Immunity 47, 1129–1141, December 19, 2017 Crown Copyright ª 2017 Published by Elsevier Inc. 1129 A number of key transcription factors were identified that control (TIM-3), Tigit, and others, which were strongly upregulated in ex- the degree of exhaustion during chronic infection, including hausted T cells, as well as transcription factors known to be T-bet (encoded by Tbx21), Blimp-1 (encoded by Prdm1), important for the differentiation of exhausted or memory T cells Eomesodermin (Eomes), von Hippel-Lindau tumor suppressor such as Prdm1 (Blimp1), Eomes, and Tcf7 (TCF1) (Figures 1B (VHL), and Foxo1 (Shin et al., 2009; Kao et al., 2011; Paley and 1C). In addition, our RNA-seq data revealed that exhausted et al., 2012; Doedens et al., 2013; Staron et al., 2014). Recently, T cells in comparison to acutely stimulated T cells expressed the transcriptional regulators TCF1, BCL6, Blimp-1, and Id2 and high amounts of Irf4 mRNA, encoding a transcription factor Id3 (via binding to E2A) were found to control the regenerative that integrates TCR signaling with cellular metabolism and clonal and migratory capacities of exhausted T cells (He et al., 2016; population expansion of effector CD8+ T cells (Man and Kallies, Im et al., 2016; Leong et al., 2016; Utzschneider et al., 2016). 2015; Man et al., 2013). High IRF4 expression in antigen-specific Thus, multiple transcription factors are co-opted in transcrip- CD8+ T cells in mice infected with chronic LCMV Docile as tional modules that differ between acute and chronic infection. compared to mice infected with acute LCMV WE was confirmed However, the molecular network that initiates, drives, and by quantitative PCR and intracellular staining, showing that high sustains the functional impairments of exhausted cells is IRF4 protein expression was established early in chronically incompletely known. stimulated T cells and was maintained up to at least 30 days after To further unravel the transcriptional circuits that underlie the establishment of chronic infection (Figures 1D and 1E). establishment of functional and metabolic exhaustion of Exhausted T cells compared to acutely stimulated T cells also T cells, we here performed transcriptional profiling of antigen- expressed elevated amounts of the AP-1 transcription factor specific CD8+ T cells isolated from mice infected with two BATF (Figures 1F and 1G) that is required for efficient DNA bind- different strains of lymphocytic choriomeningitis virus (LCMV) ing and transcriptional activity of IRF4 in T cells (Glasmacher causing acute and chronic infections, respectively. We demon- et al., 2012; Li et al., 2012). Expression of both IRF4 and BATF strate that exhausted T cells in comparison to fully functional tightly correlated with high expression of PD-1 in P14 T cells (Fig- effector and memory T cells expressed elevated amounts of ures 1H and 1I). Thus, T cell exhaustion is characterized by the the TCR-responsive transcription factors IRF4 and BATF, which elevated expression of the two TCR-responsive transcription promoted the expression of multiple inhibitory receptors factors IRF4 and BATF. including PD-1, impaired effector function, and repressed anabolic metabolism. Furthermore, exhausted T cells expressed High Amounts of IRF4 Drive T Cell Exhaustion high amounts of transcription factor NFATc1, and both NFATc1 To examine the role of IRF4 in T cell exhaustion, we generated and NFATc2 were required for the TCR-dependent induction of mice carrying floxed Irf4 alleles on a Cd4Cre transgenic back- IRF4.