Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy

Abstract

IFNγ is a cytokine with important roles in tissue homeostasis, immune and inflammatory responses and tumour immunosurveillance. Signalling by the IFNγ receptor activates the Janus kinase (JAK)–signal transducer and activator of transcription 1 (STAT1) pathway to induce the expression of classical interferon-stimulated genes that have key immune effector functions. This Review focuses on recent advances in our understanding of the transcriptional, chromatin-based and metabolic mechanisms that underlie IFNγ-mediated polarization of macrophages to an ‘M1-like’ state, which is characterized by increased pro-inflammatory activity and macrophage resistance to tolerogenic and anti-inflammatory factors. In addition, I describe the newly discovered effects of IFNγ on other leukocytes, vascular cells, adipose tissue cells, neurons and tumour cells that have important implications for autoimmunity, metabolic diseases, atherosclerosis, neurological diseases and immune checkpoint blockade cancer therapy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: IFNγ production and signalling.
Fig. 2: ‘Super-activation’ of macrophages following priming by IFNγ.
Fig. 3: IFNγ primes and induces de novo enhancer formation to promote activation of gene transcription.
Fig. 4: Chromatin regulation by IFNγ controls gene expression.
Fig. 5: IFNγ modulates key metabolic pathways.
Fig. 6: Effects of IFNγ on immune and non-immune cells.
Fig. 7: IFNγ and cancer immunotherapy.

References

  1. 1.

    Hu, X. & Ivashkiv, L. B. Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity 31, 539–550 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. 2.

    Stark, G. R. & Darnell, J. E. Jr. The JAK-STAT pathway at twenty. Immunity 36, 503–514 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  3. 3.

    Villarino, A. V., Kanno, Y. & O’Shea, J. J. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol. 18, 374–384 (2017).

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Levy, D. E., Kessler, D. S., Pine, R., Reich, N. & Darnell, J. E. Jr. Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev. 2, 383–393 (1988).

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Levy, D. E., Lew, D. J., Decker, T., Kessler, D. S. & Darnell, J. E. Jr. Synergistic interaction between interferon-alpha and interferon-gamma through induced synthesis of one subunit of the transcription factor ISGF3. EMBO J. 9, 1105–1111 (1990).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Oyler-Yaniv, J. et al. Catch and release of cytokines mediated by tumor phosphatidylserine converts transient exposure into long-lived inflammation. Mol. Cell 66, 635–647.e7 (2017).

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Kang, K. et al. Interferon-gamma represses M2 gene expression in human macrophages by disassembling enhancers bound by the transcription factor MAF. Immunity 47, 235–250.e4 (2017). This study reveals mechanisms by which IFNγ represses gene transcription and identifies the functional importance of IFNγ-repressed genes.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Langlais, D., Barreiro, L. B. & Gros, P. The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation. J. Exp. Med. 213, 585–603 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9.

    Mancino, A. et al. A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages. Genes Dev. 29, 394–408 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. 10.

    Bancerek, J. et al. CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity 38, 250–262 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Begitt, A. et al. STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling. Nat. Immunol. 15, 168–176 (2014).

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Majoros, A. et al. Canonical and non-canonical aspects of JAK-STAT signaling: lessons from interferons for cytokine responses. Front. Immunol. 8, 29 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. 13.

    Wienerroither, S. et al. Cooperative transcriptional activation of antimicrobial genes by STAT and NF-kappaB pathways by concerted recruitment of the mediator complex. Cell Rep. 12, 300–312 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Cheon, H., Yang, J. & Stark, G. R. The functions of signal transducers and activators of transcriptions 1 and 3 as cytokine-inducible proteins. J. Interferon Cytokine Res. 31, 33–40 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

    Glass, C. K. & Natoli, G. Molecular control of activation and priming in macrophages. Nat. Immunol. 17, 26–33 (2016).

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Piccolo, V. et al. Opposing macrophage polarization programs show extensive epigenomic and transcriptional cross-talk. Nat. Immunol. 18, 530–540 (2017). This study delineates mechanisms by which IFNγ and IL-4 oppose each other’s actions during macrophage polarization and shows the extent of plasticity of polarization phenotypes genome wide.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18.

    Qiao, Y. et al. Synergistic activation of inflammatory cytokine genes by interferon-gamma-induced chromatin remodeling and toll-like receptor signaling. Immunity 39, 454–469 (2013). This study identifies the epigenetic basis for synergistic transcriptional activation of inflammatory cytokine genes by IFNγ and TLR signalling.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Qiao, Y., Kang, K., Giannopoulou, E., Fang, C. & Ivashkiv, L. B. IFN-gamma induces histone 3 lysine 27 trimethylation in a small subset of promoters to stably silence gene expression in human macrophages. Cell Rep. 16, 3121–3129 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Chen, J. & Ivashkiv, L. B. IFN-gamma abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling. Proc. Natl Acad. Sci. USA 107, 19438–19443 (2010).

    PubMed  Article  Google Scholar 

  21. 21.

    Hu, X., Chakravarty, S. D. & Ivashkiv, L. B. Regulation of interferon and Toll-like receptor signaling during macrophage activation by opposing feedforward and feedback inhibition mechanisms. Immunol. Rev. 226, 41–56 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    Karonitsch, T. et al. Interferon signals and monocytic sensitization of the interferon-gamma signaling pathway in the peripheral blood of patients with rheumatoid arthritis. Arthritis Rheumatism 64, 400–408 (2012).

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Askenase, M. H. et al. Bone-marrow-resident NK cells prime monocytes for regulatory function during infection. Immunity 42, 1130–1142 (2015). This study clearly establishes that IFNγ-mediated priming occurs in vivo and is important for host defence against pathogens.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. 24.

    Leentjens, J. et al. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am. J. Respiratory Crit. Care Med. 186, 838–845 (2012). This study demonstrates that IFNγ reverses endotoxin tolerance in vivo in human subjects.

    Article  CAS  Google Scholar 

  25. 25.

    Cheng, S. C. et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat. Immunol. 17, 406–413 (2016).

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Park, S. H. et al. Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. Nat. Immunol. 18, 1104–1116 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27.

    Shi, L. et al. The SLE transcriptome exhibits evidence of chronic endotoxin exposure and has widespread dysregulation of non-coding and coding RNAs. PloS one 9, e93846 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

    Herrero, C. et al. Reprogramming of IL-10 activity and signaling by IFN-gamma. J. Immunol. 171, 5034–5041 (2003).

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Monticelli, S. & Natoli, G. Short-term memory of danger signals and environmental stimuli in immune cells. Nat. Immunol. 14, 777–784 (2013).

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007). This study introduces the concept of epigenetic regulation into the field of endotoxin tolerance.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Ivashkiv, L. B. Epigenetic regulation of macrophage polarization and function. Trends Immunol. 34, 216–223 (2013).

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Smale, S. T., Tarakhovsky, A. & Natoli, G. Chromatin contributions to the regulation of innate immunity. Annu. Rev. Immunol. 32, 489–511 (2014).

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157–171 (2013). This study demonstrates stable remodelling of chromatin at de novo enhancers induced by immune stimuli, including IFNγ, and helps pioneer the concept of short-term memory in macrophage responses.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Li, J. J. et al. IL-27/IFN-gamma induce MyD88-dependent steroid-resistant airway hyperresponsiveness by inhibiting glucocorticoid signaling in macrophages. J. Immunol. 185, 4401–4409 (2010).

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Yoshimura, A., Ito, M., Chikuma, S., Akanuma, T. & Nakatsukasa, H. Negative regulation of cytokine signaling in immunity. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a028571 (2017).

    Article  Google Scholar 

  36. 36.

    Czimmerer, Z. et al. The transcription factor STAT6 mediates direct repression of inflammatory enhancers and limits activation of alternatively polarized macrophages. Immunity 48, 75–90.e76 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. 37.

    Biswas, S. K. & Lopez-Collazo, E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 30, 475–487 (2009).

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Ho, P. C., Tsui, Y. C., Feng, X., Greaves, D. R. & Wei, L. N. NF-kappaB-mediated degradation of the coactivator RIP140 regulates inflammatory responses and contributes to endotoxin tolerance. Nat. Immunol. 13, 379–386 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 40.

    Novakovic, B. et al. β-Glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167, 1354–1368.e14 (2016). This study extends the understanding of epigenetic mechanisms in innate immune training and establishes their importance in reversal of tolerance by training stimuli.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41.

    O’Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Hu, X. et al. IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity 24, 563–574 (2006).

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Meares, G. P., Qin, H., Liu, Y., Holdbrooks, A. T. & Benveniste, E. N. AMP-activated protein kinase restricts IFN-gamma signaling. J. Immunol. 190, 372–380 (2013).

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Su, X. et al. Interferon-gamma regulates cellular metabolism and mRNA translation to potentiate macrophage activation. Nat. Immunol. 16, 838–849 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Deretic, V., Saitoh, T. & Akira, S. Autophagy in infection, inflammation and immunity. Nat. Rev. Immunol. 13, 722–737 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Van den Bossche, J. et al. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep. 17, 684–696 (2016).

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470.e13 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. 48.

    Ip, W. K. E., Hoshi, N., Shouval, D. S., Snapper, S. & Medzhitov, R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356, 513–519 (2017).

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Greer, R. L. et al. Akkermansia muciniphila mediates negative effects of IFNgamma on glucose metabolism. Nat. Commun. 7, 13329 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Goldszmid, R. S. et al. NK cell-derived interferon-gamma orchestrates cellular dynamics and the differentiation of monocytes into dendritic cells at the site of infection. Immunity 36, 1047–1059 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. 51.

    Weizman, O. E. et al. ILC1 confer early host protection at initial sites of viral infection. Cell 171, 795–808.e12 (2017).

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Soudja, S. M., Ruiz, A. L., Marie, J. C. & Lauvau, G. Inflammatory monocytes activate memory CD8(+) T and innate NK lymphocytes independent of cognate antigen during microbial pathogen invasion. Immunity 37, 549–562 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    Panduro, M., Benoist, C. & Mathis, D. Treg cells limit IFN-γ production to control macrophage accrual and phenotype during skeletal muscle regeneration. Proc. Natl Acad. Sci. USA 115, E2585–E2593 (2018).

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Moro, K. et al. Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses. Nat. Immunol. 17, 76–86 (2016).

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Pachlopnik Schmid, J. et al. Inherited defects in lymphocyte cytotoxic activity. Immunol. Rev. 235, 10–23 (2010).

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Canna, S. W. Editorial: interferon-gamma: friend or foe in systemic juvenile idiopathic arthritis and adult-onset Still’s Disease? Arthritis Rheumatol. 66, 1072–1076 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 57.

    Avau, A. et al. Systemic juvenile idiopathic arthritis-like syndrome in mice following stimulation of the immune system with Freund’s complete adjuvant: regulation by interferon-gamma. Arthritis Rheumatol. 66, 1340–1351 (2014).

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Canna, S. W. & Goldbach-Mansky, R. New monogenic autoinflammatory diseases—a clinical overview. Seminars Immunopathol. 37, 387–394 (2015).

    Article  CAS  Google Scholar 

  59. 59.

    Liu, Y. et al. Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheumatism 64, 895–907 (2012).

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Reinhardt, R. L. et al. A novel model for IFN-gamma-mediated autoinflammatory syndromes. J. Immunol. 194, 2358–2368 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Domeier, P. P. et al. IFN-gamma receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. J. Exp. Med. 213, 715–732 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62.

    Jackson, S. W. et al. B cell IFN-gamma receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6. J. Exp. Med. 213, 733–750 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Lee, S. K. et al. Interferon-gamma excess leads to pathogenic accumulation of follicular helper T cells and germinal centers. Immunity 37, 880–892 (2012).

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Manni, M. et al. Regulation of age-associated B cells by IRF5 in systemic autoimmunity. Nat. Immunol. 19, 407–419 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  65. 65.

    Chiche, L. et al. Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheumatol. 66, 1583–1595 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66.

    Hall, J. C. et al. Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases. Proc. Natl Acad. Sci. USA 109, 17609–17614 (2012).

    PubMed  Article  Google Scholar 

  67. 67.

    Ivashkiv, L. B. & Donlin, L. T. Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36–49 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Welcher, A. A. et al. Blockade of interferon-gamma normalizes interferon-regulated gene expression and serum CXCL10 levels in patients with systemic lupus erythematosus. Arthritis Rheumatol. 67, 2713–2722 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Werth, V. P. et al. Brief report: pharmacodynamics, safety, and clinical efficacy of AMG 811, a human anti-interferon-gamma antibody, in patients with discoid lupus erythematosus. Arthritis Rheumatol. 69, 1028–1034 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    Touma, Z. & Gladman, D. D. Current and future therapies for SLE: obstacles and recommendations for the development of novel treatments. Lupus Sci. Med. 4, e000239 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Chong, W. P. et al. NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-gamma-IL-27 axis. J. Exp. Med. 212, 1739–1752 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    Koblish, H. K., Hunter, C. A., Wysocka, M., Trinchieri, G. & Lee, W. M. Immune suppression by recombinant interleukin (rIL)-12 involves interferon gamma induction of nitric oxide synthase 2 (iNOS) activity: inhibitors of NO generation reveal the extent of rIL-12 vaccine adjuvant effect. J. Exp. Med. 188, 1603–1610 (1998).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    Tarrant, T. K. et al. Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis. J. Exp. Med. 189, 219–230 (1999).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Hall, A. O. et al. The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37, 511–523 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75.

    Levine, A. G. et al. Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 546, 421–425 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Newson, J. et al. Inflammatory resolution triggers a prolonged phase of immune suppression through COX-1/mPGES-1-derived prostaglandin E2. Cell Rep. 20, 3162–3175 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Vannella, K. M. & Wynn, T. A. Mechanisms of organ injury and repair by macrophages. Annu. Rev. Physiol. 79, 593–617 (2017).

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    McLaren, J. E. & Ramji, D. P. Interferon gamma: a master regulator of atherosclerosis. Cytokine Growth Factor Rev. 20, 125–135 (2009).

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Liu, W. et al. dNK derived IFN-gamma mediates VSMC migration and apoptosis via the induction of LncRNA MEG3: a role in uterovascular transformation. Placenta 50, 32–39 (2017).

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Kataru, R. P. et al. T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34, 96–107 (2011). This study establishes a new function for IFNγ in the regulation of lymphatic vessels and lymph node function by acting directly on tissue cells.

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Harismendy, O. et al. 9p21 DNA variants associated with coronary artery disease impair interferon-gamma signalling response. Nature 470, 264–268 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. 82.

    Tabas, I. & Lichtman, A. H. Monocyte-macrophages and T cells in atherosclerosis. Immunity 47, 621–634 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  83. 83.

    Odegaard, J. I. & Chawla, A. Type 2 responses at the interface between immunity and fat metabolism. Curr. Opin. Immunol. 36, 67–72 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 84.

    Wensveen, F. M. et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 16, 376–385 (2015).

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    O’Sullivan, T. E. et al. Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance. Immunity 45, 428–441 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. 86.

    Molofsky, A. B. et al. Interleukin-33 and interferon-gamma counter-regulate group 2 innate lymphoid cell activation during immune perturbation. Immunity 43, 161–174 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. 87.

    Rajbhandari, P. et al. IL-10 signaling remodels adipose chromatin architecture to limit thermogenesis and energy expenditure. Cell 172, 218–233.e17 (2018).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Herz, J., Filiano, A. J., Smith, A., Yogev, N. & Kipnis, J. Myeloid cells in the central nervous system. Immunity 46, 943–956 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Ransohoff, R. M. How neuroinflammation contributes to neurodegeneration. Science 353, 777–783 (2016).

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. Nat.Med. 23, 1018–1027 (2017).

    PubMed  Article  CAS  Google Scholar 

  91. 91.

    Ulland, T. K. et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663.e13 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  92. 92.

    Baruch, K. et al. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease. Nat. Med. 22, 135–137 (2016).

    PubMed  Article  CAS  Google Scholar 

  93. 93.

    Kreutzfeldt, M. et al. Neuroprotective intervention by interferon-gamma blockade prevents CD8+ T cell-mediated dendrite and synapse loss. J. Exp. Med. 210, 2087–2103 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. 94.

    Sun, G. et al. gammadelta T cells provide the early source of IFN-gamma to aggravate lesions in spinal cord injury. J. Exp. Med. 215, 521–535 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95.

    Filiano, A. J. et al. Unexpected role of interferon-gamma in regulating neuronal connectivity and social behaviour. Nature 535, 425–429 (2016). This study introduces the importance of the direct action of IFNγ on neurons under physiologic conditions and delineates the importance of IFNγ for neuronal function and social behaviours.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. 96.

    Derecki, N. C. et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. 97.

    Oetjen, L. K. et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell 171, 217–228.e13 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  98. 98.

    Dunn, G. P., Koebel, C. M. & Schreiber, R. D. Interferons, immunity and cancer immunoediting. Nat. Rev. Immunol. 6, 836–848 (2006).

    PubMed  Article  CAS  Google Scholar 

  99. 99.

    Parker, B. S., Rautela, J. & Hertzog, P. J. Antitumour actions of interferons: implications for cancer therapy. Nat. Rev. Cancer 16, 131–144 (2016).

    PubMed  Article  CAS  Google Scholar 

  100. 100.

    Glasner, A. et al. NKp46 receptor-mediated interferon-gamma production by natural killer cells increases fibronectin 1 to alter tumor architecture and control metastasis. Immunity 48, 396–398 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  101. 101.

    Callahan, M. K., Postow, M. A. & Wolchok, J. D. Targeting T cell co-receptors for cancer therapy. Immunity 44, 1069–1078 (2016).

    PubMed  Article  CAS  Google Scholar 

  102. 102.

    Minn, A. J. & Wherry, E. J. Combination cancer therapies with immune checkpoint blockade: convergence on interferon signaling. Cell 165, 272–275 (2016).

    PubMed  Article  CAS  Google Scholar 

  103. 103.

    Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  104. 104.

    Fu, T., He, Q. & Sharma, P. The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res. 71, 5445–5454 (2011).

    PubMed  Article  CAS  Google Scholar 

  105. 105.

    Liakou, C. I. et al. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc. Natl Acad. Sci. USA 105, 14987–14992 (2008).

    PubMed  Article  Google Scholar 

  106. 106.

    Peng, W. et al. PD-1 blockade enhances T cell migration to tumors by elevating IFN-gamma inducible chemokines. Cancer Res. 72, 5209–5218 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107.

    Shi, L. Z. et al. Interdependent IL-7 and IFN-gamma signalling in T cell controls tumour eradication by combined alpha-CTLA-4+alpha-PD-1 therapy. Nat. Commun. 7, 12335 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108.

    Gao, J. et al. Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167, 397–404.e9 (2016). Together with references 109–112, this study establishes the pivotal role of IFNγ pathways in the efficacy of immune checkpoint blockade therapy for cancers.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  109. 109.

    Shin, D. S. et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 7, 188–201 (2017).

    PubMed  Article  CAS  Google Scholar 

  110. 110.

    Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  111. 111.

    Manguso, R. T. et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413–418 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. 112.

    Patel, S. J. et al. Identification of essential genes for cancer immunotherapy. Nature 548, 537–542 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    Benci, J. L. et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167, 1540–1554.e12 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. 114.

    Garcia-Diaz, A. et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 19, 1189–1201 (2017).

    PubMed  Article  CAS  Google Scholar 

  115. 115.

    Nirschl, C. J. et al. IFNgamma-dependent tissue-immune homeostasis is co-opted in the tumor microenvironment. Cell 170, 127–141.e15 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  116. 116.

    Zaidi, M. R. et al. Interferon-gamma links ultraviolet radiation to melanomagenesis in mice. Nature 469, 548–553 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. 117.

    Kammertoens, T. et al. Tumour ischaemia by interferon-gamma resembles physiological blood vessel regression. Nature 545, 98–102 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

    Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. 119.

    Overacre-Delgoffe, A. E. et al. Interferon-gamma drives Treg fragility to promote anti-tumor immunity. Cell 169, 1130–1141.e11 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  120. 120.

    Hannesdottir, L. et al. Lapatinib and doxorubicin enhance the Stat1-dependent antitumor immune response. Eur. J. Immunol. 43, 2718–2729 (2013).

    PubMed  Article  CAS  Google Scholar 

  121. 121.

    Stagg, J. et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc. Natl Acad. Sci. USA 108, 7142–7147 (2011).

    PubMed  Article  CAS  Google Scholar 

  122. 122.

    Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).

    PubMed  Article  CAS  Google Scholar 

  123. 123.

    Wang, W. et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165, 1092–1105 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Institutes of Health.

Reviewer information

Nature Reviews Immunology thanks T. Decker, G. Trinchieri and P. Hertzog for their assistance with the peer review of this manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Lionel B. Ivashkiv.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

IFNγ signature

A pattern of elevated expression of canonical IFNγ target genes in inflamed tissues; it is often detected in samples from patients with autoimmune disease.

Endotoxin tolerance

Classically, a macrophage cell state in which prior exposure to lipopolysaccharide (LPS; an endotoxin) renders inflammatory nuclear factor-κB (NF-κB) target genes refractory to induction by subsequent LPS challenge. Tolerance can be induced by various inflammatory factors such as tumour necrosis factor (TNF), IL-1 and Toll-like receptor (TLR) ligands, and tolerized cells are resistant to multiple cell activators.

Interferon-stimulated gene factor 3

(ISGF3). A transcription factor complex comprising signal transducer and activator of transcription 1 (STAT1), STAT2 and interferon regulatory factor 9 (IRF9) that binds to interferon-stimulated response elements and regulates the expression of interferon-stimulated genes. ISGF3 is predominantly activated by type I interferons.

Latent enhancers

Enhancers that are inactive and associated with closed chromatin in resting myeloid cells. During cell activation, chromatin at latent enhancers becomes accessible, and they bind to transcription factors and drive expression of associated genes.

M2 macrophage

A type of macrophage that has been polarized by IL-4, IL-13, IL-10, glucocorticoids or various anti-inflammatory factors. M2 macrophages exhibit a range of phenotypes related to resolution of inflammation, wound healing and tissue remodelling.

Mitophagy

The selective degradation of mitochondria by autophagy.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ivashkiv, L.B. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol 18, 545–558 (2018). https://doi.org/10.1038/s41577-018-0029-z

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing