Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection.
Acute Disease
Adolescent
Adult
Aged
Antiviral Agents
/ pharmacology
Ataxia Telangiectasia Mutated Proteins
/ metabolism
CD8-Positive T-Lymphocytes
/ immunology
Chronic Disease
Epigenesis, Genetic
/ drug effects
Gene Expression Profiling
Gene Regulatory Networks
/ drug effects
Glucose
/ metabolism
Hepatitis C
/ blood
Histone Methyltransferases
/ metabolism
Humans
Lymphocyte Activation
/ drug effects
Middle Aged
Mitochondria
/ drug effects
Principal Component Analysis
Signal Transduction
/ drug effects
Transcription, Genetic
/ drug effects
Tumor Suppressor Protein p53
/ metabolism
Young Adult
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
30 01 2020
30 01 2020
Historique:
received:
25
07
2018
accepted:
11
12
2019
entrez:
1
2
2020
pubmed:
1
2
2020
medline:
14
4
2020
Statut:
epublish
Résumé
Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer.
Identifiants
pubmed: 32001678
doi: 10.1038/s41467-019-14137-7
pii: 10.1038/s41467-019-14137-7
pmc: PMC6992697
doi:
Substances chimiques
Antiviral Agents
0
Tumor Suppressor Protein p53
0
Histone Methyltransferases
EC 2.1.1.-
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
604Références
Bowen, D. G. & Walker, C. M. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436, 946–952 (2005).
pubmed: 16107834
doi: 10.1038/nature04079
Rehermann, B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat. Med. 19, 859–868 (2013).
pubmed: 23836236
pmcid: 4482132
doi: 10.1038/nm.3251
Mueller, S. N. & Ahmed, R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc. Natl Acad. Sci. USA 106, 8623–8628 (2009).
pubmed: 19433785
doi: 10.1073/pnas.0809818106
Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).
pubmed: 19043418
doi: 10.1038/ni.1679
Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015).
pubmed: 25797516
pmcid: 4393798
doi: 10.1016/j.it.2015.02.008
McKinney, E. F. & Smith, K. G. C. Metabolic exhaustion in infection, cancer and autoimmunity. Nat. Immunol. 19, 213–221 (2018).
pubmed: 29403049
doi: 10.1038/s41590-018-0045-y
Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).
pubmed: 27789799
pmcid: 5497589
doi: 10.1126/science.aae0491
Klebanoff, C. A., Gattinoni, L. & Restifo, N. P. CD8+ T-cell memory in tumor immunology and immunotherapy. Immunol. Rev. 211, 214–224 (2006).
pubmed: 16824130
pmcid: 1501075
doi: 10.1111/j.0105-2896.2006.00391.x
Chihara, N. et al. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558, 454–459 (2018).
pubmed: 29899446
pmcid: 6130914
doi: 10.1038/s41586-018-0206-z
Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).
pubmed: 16382236
doi: 10.1038/nature04444
Penna, A. et al. Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 45, 588–601 (2007).
pubmed: 17326153
doi: 10.1002/hep.21541
Wieland, D. et al. TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation. Nat. Commun. 8, 15050 (2017).
pubmed: 28466857
pmcid: 5418623
doi: 10.1038/ncomms15050
Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).
pubmed: 27789795
pmcid: 5484795
doi: 10.1126/science.aaf2807
Patsoukis, N. et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 6, 6692 (2015).
pubmed: 25809635
pmcid: 4389235
doi: 10.1038/ncomms7692
Chang, C. H. & Pearce, E. L. Emerging concepts of T cell metabolism as a target of immunotherapy. Nat. Immunol. 17, 364–368 (2016).
pubmed: 27002844
pmcid: 4990080
doi: 10.1038/ni.3415
Bengsch, B. et al. Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells. Immunity 48, 1029–1045.e5 (2018).
pubmed: 29768164
pmcid: 6010198
doi: 10.1016/j.immuni.2018.04.026
Wang, R. & Green, D. R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012).
pubmed: 22990888
doi: 10.1038/ni.2386
Chang, C.-H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).
pubmed: 23746840
pmcid: 3804311
doi: 10.1016/j.cell.2013.05.016
Phan, A. T. et al. Constitutive glycolytic metabolism supports CD8+ T cell effector memory differentiation during viral infection. Immunity 45, 1024–1037 (2016).
pubmed: 27836431
pmcid: 5130099
doi: 10.1016/j.immuni.2016.10.017
Gubser, P. M. et al. Rapid effector function of memory CD8+T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14, 1064–1072 (2013).
pubmed: 23955661
doi: 10.1038/ni.2687
Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).
pubmed: 19494812
pmcid: 2803086
doi: 10.1038/nature08097
van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).
pubmed: 22206904
doi: 10.1016/j.immuni.2011.12.007
Fisicaro, P. et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat. Med. 23, 327–336 (2017).
pubmed: 28165481
doi: 10.1038/nm.4275
Schurich, A. et al. Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host. Cell Rep. 16, 1243–1252 (2016).
pubmed: 27452473
pmcid: 4977274
doi: 10.1016/j.celrep.2016.06.078
Bengsch, B. et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45, 358–373 (2016).
pubmed: 27496729
pmcid: 4988919
doi: 10.1016/j.immuni.2016.07.008
Wolski, D. et al. Early transcriptional divergence marks virus-specific primary human CD8+ T cells in chronic versus acute infection. Immunity 47, 648–663 (2017).
pubmed: 29045899
pmcid: 5708133
doi: 10.1016/j.immuni.2017.09.006
Fisicaro, P., Boni, C., Barili, V., Laccabue, D. & Ferrari, C. Strategies to overcome HBV-specific T cell exhaustion: checkpoint inhibitors and metabolic re-programming. Curr. Opin. Virol. 30, 1–8 (2018).
pubmed: 29414066
doi: 10.1016/j.coviro.2018.01.003
Vincent, E. E. et al. Mitochondrial phosphoenolpyruvate carboxykinase regulates metabolic adaptation and enables glucose-independent tumor growth. Mol. Cell 60, 195–207 (2015).
pubmed: 26474064
doi: 10.1016/j.molcel.2015.08.013
Ho, P.-C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015).
pubmed: 26321681
pmcid: 4567953
doi: 10.1016/j.cell.2015.08.012
Kruiswijk, F., Labuschagne, C. F. & Vousden, K. H. P53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol. 16, 393–405 (2015).
pubmed: 26122615
doi: 10.1038/nrm4007
Muñoz-Fontela, C., Mandinova, A., Aaronson, S. A. & Lee, S. W. Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat. Rev. Immunol. 16, 741–750 (2016).
pubmed: 27667712
pmcid: 5325695
doi: 10.1038/nri.2016.99
Canman, C. E. et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281, 1677–1679 (1998).
pubmed: 9733515
doi: 10.1126/science.281.5383.1677
Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).
pubmed: 19847258
pmcid: 2906700
doi: 10.1038/nature08467
Lanna, A., Henson, S. M., Escors, D. & Akbar, A. N. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat. Immunol. 15, 965–972 (2014).
pubmed: 25151490
pmcid: 4190666
doi: 10.1038/ni.2981
Akbar, A. N., Henson, S. M. & Lanna, A. Senescence of T lymphocytes: implications for enhancing human immunity. Trends Immunol. 37, 866–876 (2016).
pubmed: 27720177
doi: 10.1016/j.it.2016.09.002
Guo, Z., Kozlov, S., Lavin, M. F., Person, M. D. & Paull, T. T. ATM activation by oxidative stress. Science 330, 517–521 (2010).
pubmed: 20966255
doi: 10.1126/science.1192912
Ditch, S. & Paull, T. T. The ATM protein kinase and cellular redox signaling: beyond the DNA damage response. Trends Biochem. Sci. 37, 15–22 (2012).
pubmed: 22079189
doi: 10.1016/j.tibs.2011.10.002
pmcid: 22079189
Zhou, X. et al. Resveratrol regulates mitochondrial reactive oxygen species homeostasis through Sirt3 signaling pathway in human vascular endothelial cells. Cell Death Dis. 5, e1576 (2014).
pubmed: 25522270
pmcid: 4454164
doi: 10.1038/cddis.2014.530
Truong, V. L., Jun, M. & Jeong, W. S. Role of resveratrol in regulation of cellular defense systems against oxidative stress. BioFactors 44, 36–49 (2018).
pubmed: 29193412
doi: 10.1002/biof.1399
pmcid: 29193412
Brudvik, K. W. & Taskén, K. Modulation of T cell immune functions by the prostaglandin E(2) - cAMP pathway in chronic inflammatory states. Br. J. Pharmacol. 166, 411–419 (2012).
pubmed: 22141738
pmcid: 3417476
doi: 10.1111/j.1476-5381.2011.01800.x
Quigley, M. et al. Transcriptional analysis of HIV-specific CD8+T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat. Med. 16, 1147–1151 (2010).
pubmed: 20890291
pmcid: 3326577
doi: 10.1038/nm.2232
Meek, D. W. & Anderson, C. W. Posttranslational modification of p53: cooperative integrators of function. Cold Spring Harb. Perspect. Biol. 1, a000950 (2009).
pubmed: 20457558
pmcid: 2882125
doi: 10.1101/cshperspect.a000950
Medvedeva, Y. A. et al. EpiFactors: a comprehensive database of human epigenetic factors and complexes. Database 2015, bav067 (2015).
pubmed: 26153137
pmcid: 4494013
doi: 10.1093/database/bav067
Black, J. C., Van Rechem, C. & Whetstine, J. R. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol. Cell 48, 491–507 (2012).
pubmed: 23200123
doi: 10.1016/j.molcel.2012.11.006
Casciello, F., Windloch, K., Gannon, F. & Lee, J. S. Functional role of G9a histone methyltransferase in cancer. Front. Immunol. 6, 487 (2015).
pubmed: 26441991
pmcid: 4585248
doi: 10.3389/fimmu.2015.00487
Lund, K., Adams, P. D. & Copland, M. EZH2 in normal and malignant hematopoiesis. Leukemia 28, 44–49 (2014).
pubmed: 24097338
doi: 10.1038/leu.2013.288
Snell, L. M., McGaha, T. L. & Brooks, D. G. Type I interferon in chronic virus infection and cancer. Trends Immunol. 38, 542–557 (2017).
pubmed: 28579323
doi: 10.1016/j.it.2017.05.005
Wong, M.-T. & Chen, S. S.-L. Emerging roles of interferon-stimulated genes in the innate immune response to hepatitis C virus infection. Cell. Mol. Immunol. 13, 11–35 (2016).
pubmed: 25544499
doi: 10.1038/cmi.2014.127
Radziewicz, H. et al. Impaired hepatitis C virus (HCV)-specific effector CD8+ T cells undergo massive apoptosis in the PEripheral Blood during Acute HCV infection and in the liver during the chronic phase of infection. J. Virol. 82, 9808–9822 (2008).
pubmed: 18667503
pmcid: 2566282
doi: 10.1128/JVI.01075-08
Wesselborg, S., Janssen, O. & Kabelitz, D. Induction of activation-driven death (Apoptosis) in activated but not resting peripheral blood T cells. J. Immunol. 150, 4338–4345 (1993).
pubmed: 8482839
Van Parijs, L., Ibraghimov, A. & Abbas, A. K. The roles of costimulation and Fas in T cell apoptosis and peripheral tolerance. Immunity 4, 321–328 (1996).
pubmed: 8624822
doi: 10.1016/S1074-7613(00)80440-9
Yoon, K. W. et al. Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science 349, 1261669–1261669 (2015).
pubmed: 26228159
pmcid: 5215039
doi: 10.1126/science.1261669
Banerjee, A. et al. Lack of p53 augments antitumor functions in cytolytic T cells. Cancer Res. 76, 5229–5240 (2016).
pubmed: 27466285
pmcid: 5026612
doi: 10.1158/0008-5472.CAN-15-1798
Martinez, G. J. et al. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity 42, 265–278 (2015).
pubmed: 25680272
pmcid: 4346317
doi: 10.1016/j.immuni.2015.01.006
Sadler, A. J. & Williams, B. R. G. Interferon-inducible antiviral effectors. Nat. Rev. Immunol. 8, 559–568 (2008).
pubmed: 18575461
pmcid: 2522268
doi: 10.1038/nri2314
Narita, M. et al. A novel role for high-mobility group A proteins in cellular senescence and heterochromatin formation. Cell 126, 503–514 (2006).
pubmed: 16901784
doi: 10.1016/j.cell.2006.05.052
Kakaradov, B. et al. Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing. Nat. Immunol. 18, 422–432 (2017).
pubmed: 28218746
pmcid: 5360497
doi: 10.1038/ni.3688
Henning, A. N., Roychoudhuri, R. & Restifo, N. P. Epigenetic control of CD8+ T cell differentiation. Nat. Rev. Immunol. 18, 340–356 (2018).
pubmed: 29379213
pmcid: 6327307
doi: 10.1038/nri.2017.146
de Araújo-Souza, P. S., Hanschke, S. C. H. & Viola, J. P. B. Epigenetic control of interferon-gamma expression in CD8 T cells. J. Immunol. Res. 2015, 1–7 (2015).
doi: 10.1155/2015/849573
Gray, S. M., Kaech, S. M. & Staron, M. M. The interface between transcriptional and epigenetic control of effector and memory CD8(+) T-cell differentiation. Immunol. Rev. 261, 157–168 (2014).
pubmed: 25123283
pmcid: 4267690
doi: 10.1111/imr.12205
Gray, S. M., Amezquita, R. A., Guan, T., Kleinstein, S. H. & Kaech, S. M. Polycomb repressive complex 2-mediated chromatin repression guides effector CD8+t cell terminal differentiation and loss of multipotency. Immunity 46, 596–608 (2017).
pubmed: 28410989
pmcid: 5457165
doi: 10.1016/j.immuni.2017.03.012
Scheer, S. & Zaph, C. The lysine methyltransferase G9a in immune cell differentiation and function. Front. Immunol. 8, 429 (2017).
pubmed: 28443098
pmcid: 5387087
doi: 10.3389/fimmu.2017.00429
Chang, S. & Aune, T. M. Dynamic changes in histone-methylation ‘marks’ across the locus encoding interferon-gamma during the differentiation of T helper type 2 cells. Nat. Immunol. 8, 723–731 (2007).
pubmed: 17546034
doi: 10.1038/ni1473
Müller, H. et al. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev. 15, 267–285 (2001).
pubmed: 11159908
pmcid: 312619
doi: 10.1101/gad.864201
Kim, K. H. & Roberts, C. W. M. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).
pubmed: 4918227
pmcid: 4918227
doi: 10.1038/nm.4036
Martin, B. et al. Restoration of HCV-specific CD8+ T cell function by interferon-free therapy. J. Hepatol. 61, 538–543 (2014).
pubmed: 24905492
doi: 10.1016/j.jhep.2014.05.043
Callendret, B. et al. Persistent hepatitis C viral replication despite priming of functional CD8+ T cells by combined therapy with a vaccine and a direct-acting antiviral. Hepatology 63, 1442–1454 (2016).
pubmed: 26513111
doi: 10.1002/hep.28309
Missale, G. et al. Lack of full CD8 functional restoration after antiviral treatment for acute and chronic hepatitis C virus infection. Gut 61, 1076–1084 (2012).
pubmed: 22337949
doi: 10.1136/gutjnl-2011-300515
Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).
pubmed: 17950003
doi: 10.1016/j.immuni.2007.09.006
Doering, T. A. et al. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37, 1130–1144 (2012).
pubmed: 23159438
pmcid: 3749234
doi: 10.1016/j.immuni.2012.08.021
Saeed, A. I. et al. TM4: A free, open-source system for microarray data management and analysis. Biotechniques 34, 374–378 (2003).
pubmed: 12613259
doi: 10.2144/03342mt01
Martini, P., Sales, G., Massa, M. S., Chiogna, M. & Romualdi, C. Along signal paths: an empirical gene set approach exploiting pathway topology. Nucleic Acids Res. 41, e19–e19 (2013).
pubmed: 23002139
doi: 10.1093/nar/gks866
Sales, G., Calura, E., Martini, P. & Romualdi, C. Graphite Web: web tool for gene set analysis exploiting pathway topology. Nucleic Acids Res. 41, W89–W97 (2013).
pubmed: 23666626
pmcid: 3977659
doi: 10.1093/nar/gkt386
Subramanian, A., Kuehn, H., Gould, J., Tamayo, P. & Mesirov, J. P. GSEA-P: a desktop application for gene set enrichment analysis. Bioinformatics 23, 3251–3253 (2007).
pubmed: 17644558
doi: 10.1093/bioinformatics/btm369
Merico, D., Isserlin, R., Stueker, O., Emili, A. & Bader, G. D. Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. PLoS ONE 5, e13984 (2010).
pubmed: 21085593
pmcid: 2981572
doi: 10.1371/journal.pone.0013984
Saito, R. et al. A travel guide to Cytoscape plugins. Nat. Methods 9, 1069–1076 (2012).
pubmed: 23132118
pmcid: 3649846
doi: 10.1038/nmeth.2212
Szklarczyk, D. et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43, D447–D452 (2015).
pubmed: 25352553
doi: 10.1093/nar/gku1003
Cossarizza, A. et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies. Eur. J. Immunol. 47, 1584–1797 (2017).
pubmed: 29023707
doi: 10.1002/eji.201646632