Regulation of Interferon‐γ During Innate and Adaptive Immune Responses

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Abstract

Interferon‐γ (IFN‐γ) is crucial for immunity against intracellular pathogens and for tumor control. However, aberrant IFN‐γ expression has been associated with a number of autoinflammatory and autoimmune diseases. This cytokine is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by Th1 CD4 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen‐specific immunity develops. Herein, we briefly review the functions of IFN‐γ, the cells that produce it, the cell extrinsic signals that induce its production and influence the differentiation of naïve T cells into IFN‐γ‐producing effector T cells, and the signaling pathways and transcription factors that facilitate, induce, or repress production of this cytokine. We then review and discuss recent insights regarding the molecular regulation of IFN‐γ, focusing on work that has led to the identification and characterization of distal regulatory elements and epigenetic modifications with the IFN‐γ locus (Ifng) that govern its expression. The epigenetic modifications and three‐dimensional structure of the Ifng locus in naive CD4 T cells, and the modifications they undergo as these cells differentiate into effector T cells, suggest a model whereby the chromatin architecture of Ifng is poised to facilitate either rapid opening or silencing during Th1 or Th2 differentiation, respectively.

Introduction

The canonical Th1 cytokine, interferon‐γ (IFN‐γ), is critical for innate and adaptive immunity against viral and intracellular bacterial infections. In humans, genetic deficiencies in the interleukin (IL)‐12/IL‐23/IFN‐γ pathways that result in decreased IFN‐γ induction or signaling are associated with strikingly increased susceptibility to mycobacterial infections (Filipe‐Santos et al., 2006). Susceptibility to what are normally weakly pathogenic mycobacterial strains is greatly increased in such patients, whereas susceptibility to the more pathogenic mycobacteria that cause leprosy and tuberculosis has been observed less frequently and primarily in individuals with incomplete loss‐of‐function mutations in these pathways (Casanova and Abel, 2002). Systemic infections with Salmonella are also more common (de Jong et al., 1998), but, unlike the risk for mycobacterial infection, are most often observed in those with defects in IL‐12/IL‐23 production or signaling rather than IFN‐γ signaling; this difference suggests that risk for Salmonella infection may result both from a defect in IFN‐γ production and the production of other cytokines, like IL‐17 (MacLennan et al., 2004).

IFN‐γ is also involved in tumor control (Ikeda 2002, Rosenzweig 2005). IFN‐γ directly enhances the immunogenicity of tumor cells and stimulates the immune response against transformed cells. Human tumors can evade this form of control by becoming unresponsive to IFN‐γ (Kaplan et al., 1998).

Mice with targeted genetic deficiencies resulting in the loss of IFN‐γ induction, production, or responsiveness are highly susceptible to infections due to intracellular bacteria, including mycobacteria, Salmonella (John et al., 2002), Listeria (Harty and Bevan, 1995), intracellular protozoans (including Toxoplasma and Leishmania), and certain viruses (Dalton 1993, Huang 1993, Jouanguy 1999). Such mice also display a greater range, number, and aggressiveness of naturally occurring and induced tumors (Kaplan et al., 1998).

The importance of IFN‐γ in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFN‐γ, either directly or indirectly, upregulates both major histocompatibility complex (MHC) class I and class II antigen presentation by increasing expression of subunits of MHC class I and II molecules, TAP1/2, invariant chain, and the expression and activity of the proteasome. IFN‐γ also contributes to macrophage activation by increasing phagocytosis and priming the production of proinflammatory cytokines and potent antimicrobials, including superoxide radicals, nitric oxide, and hydrogen peroxide (Boehm et al., 1997). As described below, IFN‐γ also controls the differentiation of naive CD4 T cells into Th1 effectors, which mediate cellular immunity against viral and intracellular bacterial infections. Although necessary for clearing many types of infections, excess IFN‐γ has been associated with a pathogenic role in chronic autoimmune and autoinflammatory diseases, including inflammatory bowel disease, multiple sclerosis, and diabetes mellitus (Bouma 2003, Neurath 2002, Skurkovich 2003). IFN‐γ enhances lymphocyte recruitment and prolonged activation in tissues (Hill 2002, Savinov 2001). Thus, the induction, duration, and amount of IFN‐γ produced must be closely controlled and delicately balanced for optimum host wellness.

The primary sources of IFN‐γ are natural killer (NK) cells and natural killer T (NKT) cells, which are effectors of the innate immune response, and CD8 and CD4 Th1 effector T cells of the adaptive immune system. NK and NKT cells constitutively express IFN‐γ mRNA, which allows for rapid induction and secretion of IFN‐γ on infection. In contrast to NK and NKT cells, naive CD4 and CD8 T cells produce little IFN‐γ immediately following their initial activation. However, naive CD4 and CD8 T cells can gain the ability to efficiently transcribe the gene encoding IFN‐γ (IFNG in humans and Ifng in mice) over several days in a process that is dependent on their proliferation, differentiation, upregulation of IFN‐γ‐promoting transcription factors, and remodeling of chromatin within the Ifng locus. Naive CD8 T cells are programmed to differentiate into IFN‐γ‐producing cytotoxic effectors by default, whereas CD4 T cells can differentiate into a number of effector lineages, of which only Th1 CD4 effector T cells produce substantial amounts of IFN‐γ. The process of effector differentiation in CD4 T cells, and to a lesser extent in CD8 T cells, is influenced by the nature of the infecting pathogen and the cytokine milieu emanating from the innate immune system in response to the pathogen. These differences in priming conditions in turn can result in stable changes to the chromatin structure of the gene encoding IFN‐γ, either facilitating high‐level expression in Th1 CD4 and CD8 effector T cells or silencing expression in other effector lineages.

Section snippets

NK cells

NK cells are a key component of the innate immune system providing early cellular defense against viruses and other intracellular pathogens, and contributing to the early detection and destruction of transformed host cells. NK cells develop in the bone marrow from a common lymphoid progenitor that also gives rise to B and T cells. NK cells express inhibitory receptors that recognize MHC class I molecules, which are expressed by all nucleated cells, serve as a marker for “self,” and inhibit NK

NK receptors provide a dynamic rheostat to control NK cell responses

The cytoplasmic storage of lytic granules and continual transcription of effector cytokines, including Ifng, position NK cells to respond within minutes to hours on activation, thereby contributing to early stages of immunity to infection. A fine balance of activating and inhibitory receptors are involved in the control of NK cell responses, and several of the receptors and downstream signaling events are shared with receptors found in other cells such as T cells (reviewed by Lanier 2005,

Control of IFN‐γ Production by NKT Cells

NKT cells are activated on TCR recognition of lipid antigens presented by CD1d. The ability of NKT cells to produce large amounts of both Th1 and Th2 cytokines is well documented and contrasts sharply with conventional T cells, which produce one or the other. Nearly all unstimulated NKT cells transcribe Ifng and Il4 (the gene encoding IL‐4) and well over half transcribe message for both cytokines (Matsuda 2003, Stetson 2003), indicating that the transcription factors and epigenetic status

Signaling Pathways in the Differentiation of CD4 and CD8 T Cells

As individual CD4 T cells commit to the Th1 or Th2 effector lineage to the exclusion of the other lineage, they have provided a well‐utilized model in which to study cellular and molecular events involved in cell fate choices. Much less is known regarding the Th17 fate choice, although knowledge in this area is rapidly accruing. (For a review of Th17 differentiation, see Harrington et al., 2006.) Th2 differentiation has also been reviewed (Ansel 2003, Ansel 2006, Barbulescu 1998, Lee 2006,

Transcription Factors Downstream of the TCR, Activating NK Receptors, and Cytokine Receptors

Signaling cascades relay information from receptors on the plasma membrane through the cytoplasm and into the nucleus by inducing the expression, posttranslational modification, and/or nuclear translocation of transcription factors. Transcription factors may activate expression by recruiting RNA polymerase‐containing complexes to target genes, by recruiting protein complexes that alter chromatin structure such that the binding of other transcriptional activators is facilitated, or by a

Epigenetic Processes Govern Plasticity of Cell Fate Choices and Help to Identify Distal Regulatory Elements

In principle, the transcription factors that function as “master regulators” of T and NK cell effector function could be both necessary and sufficient for the initiation and faithful propagation of their respective effector lineages. In practice, transcription factors must bind to their recognition sites within regulatory elements and then recruit general transcriptional activators or repressors to regulate gene transcription.

The ability of NK and NKT cells to rapidly produce substantial

Transcriptional Regulatory Elements Within the Ifng Gene

We will begin by reviewing the promoter and intronic regulatory elements, the transcription factors binding to them, their functions, and the epigenetic modifications to these regions that are typical of naive and effector T cells and NK cells. Then in the following sections, we will discuss newer information on the structure of the extended Ifng locus, distal regulatory elements within the locus, and what is known regarding their functions.

Functional Analysis of Candidate Distal Regulatory Elements in the Ifng Locus

The ability of these CNSs to function as enhancers has been evaluated primarily by in vitro transfection studies. In these studies, CNSs have been linked to the Ifng gene or reporter genes driven by the Ifng promoter, and their ability to enhance expression is determined following transfection of these constructs into NK and T cell lines or into primary CD4 and CD8 T cells. IfngCNS‐6 and IfngCNS‐22 enhance Ifng expression in each of these cell types, whereas other IfngCNSs are more limited in

Conclusions and Future Directions

IFN‐γ is crucial for immunity against viral and intracellular bacterial infections and tumor control; however, aberrant IFN‐γ expression has been associated with a number of autoinflammatory and autoimmune diseases. During infection, the innate recognition of pathogens leads to the production of IFN‐γ by NK and/or NKT cells, which in turn influences the generation of IFN‐γ‐producing CD4 and CD8 T cells. In NK and NKT cells, the Ifng locus is open and accessible, allowing them to produce IFN‐γ

Acknowledgments

The authors’ work described herein was supported by NIH grants AI071272 and HD18184 and a grant from the March of Dimes. JRS was supported by predoctoral training grants from the NIH (CA009537) and Cancer Research Institute.

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