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Review
. 2018 Sep;18(9):545-558.
doi: 10.1038/s41577-018-0029-z.

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

Lionel B Ivashkiv  1   2
Affiliations
Review

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

Lionel B Ivashkiv. Nat Rev Immunol. 2018 Sep.

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.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Fig. 1 |
Fig. 1 |. IFNγ production and signalling.
IFNγ is produced by innate-like lymphocytes, including group 1 innate lymphoid cells (ILC1s), and by adaptive lymphocytes, including T helper 1 (TH1) cells and cytotoxic T lymphocytes (CTLs), in response to cytokine and antigen stimulation. IFNγ acts on its receptor to induce rapid and transient Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signalling and interferon-stimulated gene (ISG) induction. Over time, the cellular IFNγ response evolves by impacting the expression and function of various enzymes and regulators of metabolism, chromatin and transcription to induce a reprogrammed cellular state that is characterized not only by its gene expression profile but also by altered responsiveness to environmental challenges. GAS, IFNγ activation site; IFNγR, IFNγ receptor; IRF, interferon regulatory factor; TCR, T cell receptor.
Fig. 2 |
Fig. 2 |. ‘Super-activation’ of macrophages following priming by IFNγ.
Polarization of macrophages by IFNγ results in their increased responsiveness to pro-inflammatory stimuli (such as lipopolysaccharide (LPS) or type I interferons) and resistance to anti-inflammatory stimuli (such as IL-4, IL-10 and glucocorticoids). This results in ‘super-activation’ of macrophages. a | Modulation of key signalling, transcriptional and chromatin components by IFNγ mediates its cross-regulation of signalling by distinct receptors. b | IFNγ augments the transcriptional activation of a subset of pro-inflammatory genes (including TNFand IL6) by opening and priming chromatin at the gene regulatory elements while inducing resistance to anti-inflammatory signals by closing chromatin in a gene-specific manner. Ac, acetylation; co-R, co-repressor; Me3, trimethylation; NF-κB, nuclear factor-κB; PRR, pattern recognition receptor; TSS, transcription start site.
Fig. 3 |
Fig. 3 |. IFNγ primes and induces de novo enhancer formation to promote activation of gene transcription.
a | IFNγ primes pre-existing enhancers and promoters via the recruitment of signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 1 (IRF1); this is associated with increased histone acetylation and chromatin remodelling. b | IFNγ induces formation of latent enhancers by inducing transcription factors (TFs) that cooperate with transcription factor PU.1 or CCAAT-enhancer-binding protein (C/EBP) family proteins to form new enhancers. NF-κB, nuclear factor-κB; TLR, Toll-like receptor; TSS, transcriptional start site.
Fig. 4 |
Fig. 4 |. Chromatin regulation by IFNγ controls gene expression.
a | IFNγ suppresses enhancer function by decreasing histone acetylation and attenuating the recruitment of signal transducer and activator of transcription 6 (STAT6) (step 1). A subset of suppressed enhancers is bound by transcription factor MAF, and these enhancers harbour STAT6-binding motifs that exhibit decreased STAT6 occupancy after IFNγ stimulation. At a subset of MAF-bound enhancers, IFNγ-mediated downregulation of MAF expression and binding results in enhancer disassembly and refractoriness to activation by IL-4, IL-10 or glucocorticoids (step 2). b | IFNγ reverses gene tolerization by enabling opening of chromatin in response to weak upstream signals. The magnitude of gene expression is determined by the combination of signalling strength and chromatin state. LPS, lipopolysaccharide; NF-κB, nuclear factor-κB; TF, transcription factor; TLR, Toll-like receptor; TSS, transcription start site.
Fig. 5 |
Fig. 5 |. IFNγ modulates key metabolic pathways.
IFNγ suppresses growth factor and nutrient pathways to modulate activity of several central regulators of cellular metabolism, including mammalian target of rapamycin complex 1 (mTORC1), glycogen synthase kinase 3 (GSK3) and 5′-AMP-activated protein kinase (AMPK). Functionally important outcomes of metabolic regulation by IFNγ are depicted in red boxes. CREB, CCAAT-enhancer-binding protein; NF-κB, nuclear factor-κB; TLR, Toll-like receptor; TNF, tumour necrosis factor.
Fig. 6 |
Fig. 6 |. Effects of IFNγ on immune and non-immune cells.
The functional outcomes of IFNγ action on tissues and organs are determined by the integration of its effects on specialized tissue cells and on resident or infiltrating immune cells. The effects of IFNγ are context-dependent and can differ under homeostatic or disease conditions; thus, IFNγ can either suppress or promote tissue damage. a | IFNγ has general effects on various cells. b | IFNγ has effects on different immune cell populations. c | IFNγ has homeostatic and pathological effects. ABC, age-associated B cell; HLH, haemophagocytic lymphohistiocytosis; ILCs, innate lymphoid cells; TFH cell, T follicular helper cell; TH cell, T helper cell; Treg cell, regulatory T cell.
Fig. 7 |
Fig. 7 |. IFnγ and cancer immunotherapy.
IFNγ plays an important role in the effectiveness of immune checkpoint blockade (ICB). ICB blocks the interaction of programmed cell death 1 ligand 1 (PDL1), CD80 and CD86 expressed on tumour cells, tumour-associated macrophages (TAMs) and dendritic cells (DCs) with their cognate inhibitory receptors programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte antigen 4 (CTL A4) expressed on tumour-infiltrating effector T cells (including cytotoxic T lymphocytes (CTLs)). Two important consequences of ICB are increased T cell function (because of diminished inhibitory signalling that reverses their exhausted state) and increased intratumoural production of IFNγ, likely at least in part by T cells. Important IFNγ functions (red boxes) include direct effects on tumour cells to suppress proliferation and increase antigen presentation. The effects of IFNγ and ICB on the depicted cell types are listed under each cell type. The combination of increased CTL function and increased antigen presentation promotes immune-mediated tumour eradication. IFNγ also has feedback inhibitory effects (blue boxes) that can attenuate antitumour immunity; overcoming these inhibitory effects is an important goal for improving the efficacy of ICB. IDO, indoleamine 2,3-dioxygenase; TH1 cell, T helper 1 cell; TNF, tumour necrosis factor; SOCS2, suppressor of cytokine signalling 2.
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