Skip to main content
NCBI home page
Journal of Interferon & Cytokine Research logoLink to Journal of Interferon & Cytokine Research
. 2022 Dec 12;42(12):643–654. doi: 10.1089/jir.2022.0132

IFN-γ and TGF-β, Crucial Players in Immune Responses: A Tribute to Howard Young

Thierry Gauthier 1, WanJun Chen 1,✉
PMCID: PMC9917322  PMID: 36516375

Abstract

Interferon gamma (IFN-γ) and transforming growth factor beta (TGF-β), both pleiotropic cytokines, have been long studied and described as critical mediators of the immune response, notably in T cells. One of the investigators who made seminal and critical discoveries in the field of IFN-γ biology is Dr. Howard Young. In this review, we provide an overview of the biology of IFN-γ as well as its role in cancer and autoimmunity with an emphasis on Dr. Young's critical work in the field. We also describe how Dr. Young's work influenced our own research studying the role of TGF-β in the modulation of immune responses.

Keywords: IFN-gamma, TGF-beta, cytokines

Introduction

Cytokines can be defined as a broad category of small soluble proteins that mediate intracellular communication. While cytokines can be produced by many cell types, immune cells are the most important producers of these molecules. Since their discovery in the 1960–70s, a large number of cytokines have been described, regulating a wide range of processes like growth, metabolism, tissue repair, and inflammation. (Dinarello 2007). Among these cytokines, interferon gamma (IFN-γ, also known as type II interferon) was discovered in 1965 as an antiviral factor secreted by peripheral blood mononuclear cells in response to phytohemagglutinin (Wheelock 1965). Four decades after its discovery, IFN-γ is now well known as a crucial regulator of innate and adaptive immune responses.

The IFN-γ gene is located on chromosome 12q15 in humans and on the chromosome 10D2 in mice (Naylor and others 1983, 1984). IFN-γ, which is structurally similar between mammalians, is composed of a homodimer thar signals through its receptor IFN-γR1 and R2. While IFN-γ binds only to IFN-γR1, IFN-γR2 mediates its downstream signaling (Savan and others 2009). In this review, we will describe the regulation and function of IFN-γ with an emphasis on the role of Dr. Howard Young to define the regulation of IFN-γ during health and disease. Finally, we will discuss how his work has impacted our studies on the role of transforming growth factor beta (TGF-β) in the modulation of immune responses.

IFN-γ Biology

IFN-γ-producing cells

IFN-γ can be produced by a wide range of immune cells. One of the best described producers of IFN-γ are the CD4 T helper cells. This discovery has notably led to the classification of Th1/Th2 paradigm (Kasahara and others 1983; Mosmann and others 1986). Among T cells, CD8 cytotoxic T cells and γδ T cells are also known to produce large amounts of IFN-γ (Gao and others 2003; Matsushita and others 2015). Importantly, Dr. Young discovered in 1995 that natural killer cells (NK cells) also produce IFN-γ, which paved the way to discover new functions of NK cells mediated by IFN-γ (Ye and others 1995; Laouar and others 2005).

Although to a lesser extent, Dr. Young and others also demonstrated that natural killer T cells, B cells, and antigen-presenting cells could produce IFN-γ (Pang and others 1992; Yoshimoto and others 1998; Ohteki and others 1999; Flaishon and others 2000; Darwich and others 2009; Kling and others 2018).

IFN-γ signaling

As stated before, IFN-γ signals through its receptors IFN-γR1 and R2. IFN-γR1 is constitutively expressed on the surface of most cells. IFN-γR2 is expressed at much lower levels, but its expression is tightly regulated, and it regulates the activation and inhibition of growth by IFN-γ (Bach and others 1995; Pernis and others 1995; Novelli and others 1996). IFN-γ binding to IFN-γR1 leads to the recruitment of IFN-γR2 (Fig. 1). These 2 receptors are constitutively associated with the Janus kinases (JAK) 1 and 2 and upon the activation of IFN-γRs, JAK1-2 will be activated.

FIG. 1.

FIG. 1.

Open in a new tab

IFN-γ and TGF-β signaling pathways and their intersections. IFN-γ binds and signals through its receptors IFN-γR1 and 2, initiating a cascade of signaling events mediated by JAK1/2 and STAT1. STAT1 therefore binds to the promoters of several genes (including iNOS, IRF-1 and 9, or SMAD7) and induces their transcription. IRF-1 and 9 finally induce a secondary response by controlling the expression of several genes regulating immune responses. On the other hand, TGF-β signals through its receptors TGF-βR1 and 2, which activates a canonical pathway (mediated by SMAD2/3/4) or a noncanonical pathway (notably mediated by MEK/ERK), leading to the control of immune responses as well. The IFN-γ and TGF-β signaling pathways interestingly regulate one another: SMAD7 induction by IFN-γ inhibits the canonical TGF-β signaling, while MEK/ERK activation by TGF-β inhibits STAT1 phosphorylation. IFN-γ, interferon gamma; IRF1, IFN regulatory factor 1; JAK1/2, Janus kinases 1 and 2; MEK/ERK, mitogen-activated protein kinase kinase/extracellular signal-regulated kinase; STAT1, signal transducer and activator of transcription 1; TGF-β, transforming growth factor beta.

Active JAK1-2 will phosphorylate the intracellular domain of IFN-γR1-2, which leads to the recruitment of the signal transducer and activator of transcription 1 (STAT1). STAT1 is therefore phosphorylated at tyrosine 701 by JAK kinases, leading to the formation of homodimers of STAT1. pStat1 will then translocate inside the nucleus and regulate gene expression by binding to a regulatory DNA element called gamma-activated sequence (Greenlund and others 1994; de Weerd and Nguyen 2012).

One of the major negative regulators of STAT1 activation is suppressor of cytokine signaling 1 (SOCS1) and mice lacking SOCS1 die a few days after birth because of uncontrolled IFN-γ responses (Alexander and others 1999; O'Shea and Murray 2008). Mechanistically, SOCS1 Src homology 2 (SH2) domains can bind to the phosphorylated tyrosine of JAKs proteins and inhibit the recruitment of STAT1. This will result in ubiquitination and degradation of components of JAK/STAT signaling (Endo and others 1997; Kamizono and others 2001). Besides this well-known function of SOCS1, STAT1 is also regulated by activation-inactivation cycles, which are mediated by post-translational mechanisms (eg, dephosphorylation of Y701 and acetylation of lysine residues) (Hu and Ivashkiv 2009).

After activation, STAT1 targets a wide range of genes, but one of the most important is the IFN regulatory factor 1 (IRF1) (Taniguchi and others 2001). STAT1 is also an important regulator of genes involved in the regulation of cell cycle, proliferation, and metabolism (Chin and others 1996; Ramana and others 2000; Pitroda and others 2009). IFN-γR1 and 2 are expressed in a large range of nonimmune and immune cells, including CD4 and CD8 T cells, macrophages, NK cells, and dendritic cells, emphasizing its critical role in modulating innate and adaptive immune responses (de Weerd and Nguyen 2012; Gauthier and Chen 2022).

Control of IFN-γ Expression

The expression of IFN-γ is controlled by a variety of different mechanisms, including transcriptional and epigenetic mechanisms (histone modifications, miRNAs, lncRNAs, and DNA methylation) (Fenimore and Howard 2016). Many of these mechanisms are regulated by cytokines and their downstream transcription factors (Fig. 2).

FIG. 2.

FIG. 2.

Open in a new tab

Activation and repression of IFN-γ expression by cytokines and their downstream transcription factors. Several cytokines regulate IFN-γ gene expression either directly or indirectly by regulating its master transcription factor T-bet. IL-2, 4, 12, 15, 18, and 27 induce IFN-γ expression in a STAT-dependent manner, while IL-18 also induces IFN-γ in an NFκB-dependent manner. Moreover, IL-12 through STAT1/4 promotes the expression of T-bet, therefore leading to the expression of IFN-γ. Importantly, TGF-β is one of the unique cytokines that can repress the expression of T-bet, which ultimately impairs the expression of IFN-γ. IL-2, interleukin-2; NFκB, nuclear factor kappa B.

Interleukin-2

Interleukin-2 (IL-2) is a pleiotropic cytokine, well known as a crucial regulator of T and NK cells. It signals through 3 receptor subunits (alpha, beta and a common gamma chain) (Mortara and others 2018). IL-2 was first demonstrated to induce IFN-γ in human T helper and cytotoxic cells, possibly through a protein kinase C-dependent event (Kasahara and others 1983; Farrar and others 1986). Importantly, Dr. Young's group also demonstrated that IL-2 induction of STAT5 was able to induce IFN-γ expression through its binding at a regulatory element associated with epigenetic reprogramming (notably histone 3 and 4 acetylation) (Bream and others 2004).

Interestingly, this mechanism is not only limited to T and NK cells but also occurs in dendritic cells (DC) (Herr and others 2014). In addition to its effect on transcription, Dr. Young also described that IL-2 could regulate the induction of IFN-γ post-transcriptionally. Indeed, in NK cells, IL-2 promotes the stability and movement of IFN-γ mRNA from the nucleus toward the cytoplasm, therefore promoting its translation (Hodge and others 2002).

Interleukin-15

IL-15 is a heterodimeric cytokine, which triggers activation of the cytolytic function and proliferation of CD8 T cells and NK cells. Production of IL-15 by antigen-presenting cells can notably, through its heterodimeric receptor, trigger the production of IFN-γ in NK and γδ T cells (Carson and others 1995; Van Acker and others 2018).

Interleukin-18

IL-18 is a member of the IL-1 family of cytokines. IL-18 is synthesized as an immature precursor that needs to be cleaved by caspase 1 to be activated. Once activated, it signals through a heterodimeric complex, triggering the activation of a MyD88/TRAF6/TAK1/nuclear factor kappa B (NFκB) signaling pathway (Dinarello and others 2013). The main mechanisms of IFN-γ induction by IL-18 are occurring through NFκB activation (Kojima and others 1999). However, IL-18 can also induce the expression of IFN-γ through a mitogen-activated protein kinase-STAT3 pathway when combined with IL-2 (Kalina and others 2000), while in combination with IL-12 or IFN-α, it can enhance IFN-γ production by STAT4 (Matikainen and others 2001).

Interleukin-27

IL-27 is a heterodimeric cytokine composed of 2 subunits [Epstein-Barr virus-induced gene 3 (EBI3) and IL-27p28], which signal through a receptor composed of gp130 and IL-27Rα leading to the activation of the JAK/STAT pathway (Hall and others 2012). The induction of STAT1/3 activation further leads to the expression of T-bet (T-box expressed in T cells) and the enhanced production of IFN-γ in T cells (Pflanz and others 2002; Cheng and others 2022). However, the role of IL-27 in the induction of IFN-γ is more complex than what we thought at first and could be dependent on context. For example, it has been demonstrated that IL-27 receptor-deficient mice had higher pathology during infections due to heightened levels of IFN-γ (Hall and others 2012).

Interleukin-4

IL-4 is a pleiotropic cytokine regulating many aspects of immune responses. It is notably best known in T cell biology to induce the generation of Th2 cells and to repress Th1 functions (Luzina and others 2012; Lopez-Bravo and others 2013). However, and importantly, Dr. Young's group reported that IL-4, in synergy with IL-2 or IL-12, could promote the expression of IFN-γ in NK cells. This not only occurs through a STAT6-dependent pathway but also through an enhanced activation of STAT4 and 5, demonstrating a more complex role of IL-4 in the modulation of immune responses (Bream and others 2003).

Interleukin-12

Finally, IL-12 is the main and best described inducers of IFN-γ. IL-12 belongs to the IL-6 family of cytokines. IL-12 is a heterodimer composed of IL-12p40 and IL-12p35. Upon its binding to its receptors (IL-12Rβ1 and 2), IL-12 will activate JAK2 and TYK2 (Tyrosine Kinase 2), which will further activate the transcription factor STAT4 (Trinchieri 2003). IL-12 was first demonstrated to induce IFN-γ in NK cells, but later was shown to also induce it in T cells (Kobayashi and others 1989; Trinchieri 2003). STAT4 is crucial to induce IFN-γ expression in response to IL-12 (notably to keep the chromatin open), but IL-12 also requires the activation of the transcription factor T-bet by STAT1 to fully induce IFN-γ expression (Fenimore and Howard 2016).

Interestingly, Dr. Young's group also demonstrated that IL-12 regulates the synthesis of IFN-γ mRNA (leading to a “priming” of the cells), while IL-2 promotes its release to the cytoplasm (providing a second signal necessary for IFN-γ production). Importantly, the presence of both IL-12 and IL-2 is needed to promote a steady release of IFN-γ over time (Hodge and others 2002).

Transcription factors regulating IFN-γ expression

Several transcription factors have been demonstrated to promote IFN-γ expression. As described above, the STAT family of transcription, as well as T-bet play crucial roles to positively regulate IFN-γ expression in the context of cytokine stimulation. Importantly, Dr. Young's group also discovered several other transcription factors involved in the regulation of IFN-γ expression. Notably, they discovered that a single nucleotide polymorphism (at -179 of the IFN-γ promoter) is associated in the creation of a potential binding site for AP-1, leading to a higher expression of IFN-γ in response to tumor necrosis factor alpha in human T cells. This is of great importance since 4% of the African-American population possesses this mutation (Bream and others 2002).

Interestingly, AP-1, cAMP response element-binding protein (CREB), and activating transcription factor (ATF) can form a complex that activates the expression of IFN-γ in human T cells in response to Mycobacterium tuberculosis (Samten and others 2008). Treatment with dexamethasone repressed IFN-γ expression by repressing this AP-1/CREB/ATF complex (Cippitelli and others 1995). Dr. Young's group was also the first to demonstrate that the members of the NFκB family (c-rel, p50, and p65) could bind and activate the IFN-γ promoter, notably after T cell activation (Sica and others 1992, 1997). It was later discovered that, upon T cell activation, NFκB cooperates with STAT4 to induce IFN-γ expression in CD4 and CD8 T cells, a process that is dependent on T-bet in CD4 T cells, but independent of T-bet in CD8 T cells (Balasubramani and others 2010).

Strikingly, mice deficient for c-Rel showed a complete inability to develop central nervous system inflammation due to the inability of T cells to produce IFN-γ (Hilliard and others 2002). Of note, nuclear factor of activated T cells can bind to a similar site as NFκB in activated T cells, suggesting a coordination between these 2 transcription factors in regulating IFN-γ expression (Sica and others 1997; Kiani and others 2001).

Negative regulators of IFN-γ expression

Several transcription factors have been described to negatively regulate the expression of IFN-γ, including prospero-related homeobox (Prox1), downstream regulatory element antagonist modulator (DREAM), GATA3, and Ying Yang 1 (YY1) (Fenimore and Howard 2016). GATA3 is a well-known and crucial regulator of Th2 cells and has been described as one of the main IFN-γ repressors (Ferber and others 1999). Importantly, in unactivated T cells, deletion of GATA3 allows the production of IFN-γ in a T-bet-independent manner, but through the transcription factor Runx3 induction of Eomes (Yagi and others 2010). Moreover, it is now largely described that GATA3 and T-bet opposing actions lead to the differentiation of T cells toward Th1 and Th2 subsets and therefore the levels of IFN-γ expression by T cells (Murphy and Reiner 2002; Jenner and others 2009). YY1 is a zinc transcription factor that can function either as a transcriptional activator or repressor (Verheul and others 2020).

Dr. Young's laboratory demonstrated, in 2 elegant studies, that YY1 was involved in the negative regulation of IFN-γ. In the first study, they identify a binding element region in the promoter of IFN-γ (from −251 to −215), which possesses a silencer activity. They therefore identified YY1 as one of the proteins present in a complex and able to bind the IFN-γ promoter in this region (Ye and others 1994). In their follow-up study, they confirmed their findings and further proved that YY1 was able to bind to different sites into the IFN-γ promoter. One of these sites was identified as a binding site for AP-1 and the competition between AP-1 and YY1 regulated positively or negatively the expression of IFN-γ (Ye and others 1996).

Role of IFN-γ in Controlling Immune Responses During Health and Diseases

IFN-γ function during immune responses

IFN-γ can regulate and coordinate several responses in innate and adaptive immune cells. It is notably one of the main activators of proinflammatory macrophages (M1) (Hu and Ivashkiv 2009). In macrophages (and innate immune cells in general), IFN-γ (sometimes in combination with lipopolysaccharide [LPS]) will trigger the activation of IRF1 and IRF5 leading to the expression of interferon-stimulated genes, including proinflammatory genes, chemokine receptors, nitric oxide, reactive oxygen species, and chemokines (Qiao and others 2013; De Benedetti and others 2021). It also regulates macrophage functions like antimicrobicidal activity and phagocytosis, as well as metabolism (Su and others 2015; De Benedetti and others 2021).

Importantly, IFN-γ was described, early on, as inducing the major histocompatibility complex (MHC-I) and II presentation machinery in antigen-presenting cells, which further leads to the activation of the adaptive immune response. The activation of the innate immune system by IFN-γ will therefore lead to the activation of the adaptive immune response and generate a Th1 response leading to a positive feedback loop finally enforcing the expression of IFN-γ in CD4, CD8 T cells, and NK cells (Castro and others 2018). In the meantime, IFN-γ production will inhibit the generation of Th2, Th17, and Treg cells (Gajewski and Fitch 1988; Oriss and others 1997; Kelchtermans and others 2009; Caretto and others 2010; Olalekan and others 2015).

In addition to these effects of IFN-γ, Dr Young's group also demonstrated that IFN-γ is an important modulator of immune cell development. To study the role of IFN-γ in vivo, they generated a mouse model in which IFN-γ is overexpressed by inserting multiple copies of the murine IFN-γ genomic DNA containing an Igλ-chain enhancer in the first intron. These mice show an 8–15 times increase in IFN-γ in the spleen and bone marrow, as well as a dramatic increase in IL-12 levels in these organs, while the levels of IL-4 were reduced. These transgenic mice show no B cell presence in the spleen and bone marrow, as well as a dramatic decrease of myeloid progenitors in the bone marrow and T cells in the spleen.

Intriguingly, the number of single positive thymocytes was increased 2 times, suggesting a blocking of T cell migration from the thymus. The number of NK cells in the spleen and liver is also drastically reduced due to an inability of stem cells to proliferate and differentiate into NK cells, as well as an increased ability to undergo apoptosis. Importantly, these mice, at steady state, have an appearance of granulomatous lesions and residual degenerating cartilaginous masses in their bones (Young and others 1997; Shimozato and others 2002).

IFN-γ function in diseases

In cancer

Given its crucial role in modulating innate and adaptive immunity, it is not surprising that IFN-γ regulates the development of immune-mediated diseases like cancer, infections, and autoimmunity. During cancer development, IFN-γ has been described to play a crucial role in modulating antitumor immunity (Burke and Young 2019). It was first reported that tumor cells with a truncated dominant negative form of IFN-γRα displayed enhanced tumorigenicity and were resistant to LPS-induced tumor rejection.

Importantly, when these IFN-γ-resistant tumors were resected and mice were reinjected with normal tumors, they developed less immunogenicity, suggesting for the first time that IFN-γ-production/action on immune cells was critical to eradicate tumors (Dighe and others 1994). This was later confirmed when IFN-γ and its downstream transcription factor STAT1 were deleted in mice; tumor growth was dramatically increased, notably due to the deficiency of IFN-γ production by T lymphocytes (Kaplan and others 1998; Shankaran and others 2001). One of the mechanisms by which IFN-γ acts in promoting tumor rejection is through the generation of proinflammatory macrophages. Macrophages can present tumor peptides to T cells by MHC-II, therefore leading to the production of IFN-γ by T cells and the further activation of macrophages by these T cells, demonstrating a cooperative crosstalk between these cells (Corthay and others 2005).

Production of IFN-γ by Th1 will lead macrophages to produce IL-1β, IL-6, CXCL9, and CXCL10, as well as rendering them cytotoxic for cancer cells (Haabeth and others 2011). Interestingly, enforcement of the IFN-γ/STAT1 signaling in macrophages induced by DICER ablation leads to a decrease in their immunosuppressive capacity and to the recruitment of cytotoxic T cells, eventually leading to decreased tumor growth (Baer and others 2016). The induction of production of CXCL9, 10, and 11 (notably by macrophages) is important for the trafficking of T cells into tumors. Importantly, T cells fail to infiltrate the tumor site into mice deficient for IFN-γ gene (Nakajima and others 2001).

Besides these well-described effects of IFN-γ in modulating immune cells in the tumor microenvironment, IFN-γ can also inhibit the proliferation and survival of endothelial cells, leading to the destruction of blood vessels, and impaired angiogenesis, leading to the rejection of tumors (Castro and others 2018). Finally, IFN-γ can directly modulate the behavior of cancer cells. The expression of the cyclin-dependent kinase inhibitor p21 WAF1/CIP1 is induced by IFN-γ in a STAT1-dependent manner leading to the decreased proliferation of cancer cells (Chin and others 1996). Through STAT1, IFN-γ is also able to induce the expression of caspases 1, 3, and 8, as well as the secretion of FAS, FAS ligand, and TRAIL to promote cancer cell apoptosis or necroptosis (Chin and others 1997; Xu and others 1998; Fulda and Debatin 2002; Takeda and others 2002; Liu and others 2011; Thapa and others 2011).

Importantly, IFN-γ appears to be an important factor to determine the efficiency of immune checkpoint therapies (like anti-PD-1 and CTLA-4 antibodies), and modulation of IFN-γ in combination with immune checkpoint blockades could prove to be a good strategy for improving the efficiency of cancer immunotherapy (Gao and others 2016; Ayers and others 2017; Higgs and others 2018; Karachaliou and others 2018).

Despite its well-known antitumorigenic effect, it also appears that IFN-γ can have a protumorigenic effect as well. Indeed, B16F10 cancer cells treated with IFN-γ at a physiological dose in vitro, once injected into the mice, can increase the number of pulmonary metastasis (Taniguchi and others 1987). Interestingly, another group demonstrated that low-dose IFN-γ increases the stemness of non-small cell lung cancer cells resulting in increased tumor growth and lung metastasis (Song and others 2019). IFN-γ can also impact tumor immunoediting, resulting in the emergence of resistant cancer cell clones in a mechanism dependent on cytotoxic CD8 T cells (Takeda and others 2017). It can also promote tumor evasion from the immune system by downregulating the expression of some antigens (notably gp70), which decreases their ability to be lysed by CD8 T cells (Beatty and Paterson 2000).

Another means of action of IFN-γ is to regulate the expression of PD-L1 in cancer cells, therefore decreasing the infiltration of the tumor by tumor-infiltrating lymphocyte eventually leading to increased tumor growth (Abiko and others 2015). Finally, another possible mechanism of action by which IFN-γ could promote tumorigenesis is by upregulating the expression of Indolamine-2,3-dioxygenase (IDO), thereby promoting the generation of tolerogenic immune cells (Jorgovanovic and others 2020).

In autoimmunity

The role of IFN-γ has been extensively studied in autoimmune diseases. Similar to cancer development, it appears that IFN-γ can have a dual role in the development and pathogenesis of autoimmune diseases. Early studies have shown that IFN-γ at the systemic or tissue level could exacerbate the development of autoimmunity in systemic lupus erythematosus (SLE), diabetes, multiple sclerosis (MS), and eczema (Sarvetnick and others 1990; Corbin and others 1996; Carroll and others 1997; Seery and others 1997). For example, in type 1 diabetes, overexpression of IFN-γ within the β-islets exacerbates the disease, and injection of IFN-γ-producing Th1 cells is sufficient to trigger diabetes in neonatal Non-Obese Diabetic (NOD) mice (Sarvetnick and others 1990; Katz and others 1995).

In an experimental model of SLE, injection of IFN-γ worsens the disease, while administration of anti-IFN-γ is protective (Jacob and others 1987). Confirming this study, the reduction or abrogation of IFN-γ production by using heterozygous or homozygous mice deficient for IFN-γ is sufficient to protect the mice from the disease (Balomenos and others 1998). However, IFN-γ has a more controversial role in the development of MS and rheumatoid arthritis (RA) (Lees 2015). The expression of IFN-γ in MS lesions is increased, as well as in lymphocytes from the blood and cerebrospinal fluid of MS patients (Hirsch and others 1985; Benvenuto and others 1992; Lock and others 2002). Moreover, injection of IFN-γ in MS patients resulted in exacerbation of the disease associated with activation of the immune system (Panitch and others 1987).

In experimental autoimmune encephalomyelitis (EAE) models, Th1 cells are sufficient to induce the disease and appear to be crucial effectors for the development of the pathology (Jager and others 2009; Domingues and others 2010). However, some other groups reported protective effects of IFN-γ. For example, treatment of EAE SJL/J mice with a monoclonal antibody targeting IFN-γ enhanced the pathogenesis as shown by decreases in mortality, morbidity, and disease onset (Lublin and others 1993). Interestingly, when EAE was induced in IFN-γ KO mice in the BALB/c background, some mice started to develop EAE symptoms, notably characterized by increased inflammation in the central nervous system (Krakowski and Owens 1996).

A similar pattern was observed during RA, in which IFN-γ was sometimes described as promoting the disease (Mauritz and others 1988; Chu and others 2007), while in other settings, IFN-γ had an anti-inflammatory effect (Nakajima and others 1990; Vermeire and others 1997; Matthys and others 1999; Lees 2015). Therefore, it appears that the types of pathology, source of IFN-γ, its expression levels, and timing of expression, as well as its localization could all influence the effect of IFN-γ on the development of autoimmune diseases (Lees and others 2008; Lees 2015).

Although numerous studies were interested in the role of IFN-γ, many of the approaches used total knockout mice, blocking antibodies, or IFN-γ injections. However, the effect of low and steady dysregulation of IFN-γ levels was unknown. Dr. Young's group elegantly generated C57BL/6 mice with a 162 nt AU-rich element (ARE) region deletion in the 3′ untranslated region (3′UTR) of the IFN-γ gene (called ARE-Del−/−), which results in higher stability of IFN-γ mRNA and in chronic circulating serum IFN-γ levels (Hodge and others 2014).

These mice have a phenotype resembling SLE patients with increased levels of autoreactive antibodies, development of mesangioproliferative glomerulonephritis, and enhanced pDC accumulation in the bone marrow and spleen, as well as a loss of marginal zone macrophages and B cells. Interestingly, heterozygous mice did not develop these symptoms, but depletion of macrophages with clodronate was enough to trigger a similar phenotype as seen in hemizygous mice (Hodge and others 2014). When the genetic change was crossed into Balb/c mice, the mice developed a phenotype resembling aplastic anemia (decrease of at least 50% of the bone marrow cellularity) with marked decreases in myelopoiesis and erythropoiesis (Lin and others 2014). Dr. Young's group also reported a few years later that the ARE-Del−/− mice develop primary biliary cholangitis characterized by production of bile acids and antimitochondrial antibodies and portal duct inflammation.

Quite interestingly and just like the sex bias observed in patients, female mice have a much more pronounced phenotype compared to male mice. These mice have now become an important new model for understanding the human disease. The disease development appears to be largely dependent on IFN-γ producing T cells since transfer of T cells from ARE-Del−/− into Rag1−/− mice is sufficient to trigger the early stage of this disease. Importantly, crossing these mice with Ifnar1 KO mice completely abrogated their phenotype (Bae and others 2016, 2018). Finally, they observed that female mice have a largely dysregulated microbiota with marked differences in terms of microbial metabolites (eg, tryptophan metabolism, bile acid, and long-chain lipid metabolism), which are likely to activate downstream signaling from PPARs, LXRs, and FXR, providing an insight into the mechanism by which increased levels of IFN-γ can regulate the development of autoimmunity (Bae and others 2020).

IFN-γ and TGF-β

The focus of our laboratory for the past 25 years has been to decipher the role of TGF-β1 (referred as TGF-β throughout the article) in the development and modulation of the immune system during health and disease. TGF-β is a pleiotropic cytokine regulating a wide variety of cell functions, including development, activation, proliferation, differentiation, migration, and survival of immune and nonimmune cells. TGF-β is produced in the form of a precursor called the latent form of TGF-β (LTGF-β) in that the LAP (for latency associated peptide) needs to be proteolytically processed to release the active TGF-β. Several mechanisms have been indicated to be involved in the activation of TGF-β, including activation by proteins (eg, integrins, proteases, deglycosidases or thrombospondin 1) or by physicochemical factors (detergents, ionizing, and ultraviolet radiation, reactive oxygen species, physical shear, and pH variations) (Robertson and Rifkin 2016).

TGF-β, once activated, binds to the TGF-β receptor II (TGF-βRII), which forms a stable heterodimeric complex with TGF-βRI (also called ALK5) and activates the SMAD2/3 complex by phosphorylation, which normally interacts with SMAD4, eventually leading to the binding of the complex into the DNA and the regulation of gene transcription (Chen and Ten Dijke 2016; Derynck and Budi 2019) (Fig. 1). Besides this canonical signaling, TGF-β can also induce the activation of several non-SMAD (or noncanonical) signaling pathways, including PI3K/AKT, ERK, TRAF6/TAK1, JNK/P38, or the Rho-like GTPases (Zhang 2017).

Similar to IFN-γ, TGF-β and its role in modulating immune responses have been extensively studied. TGF-β has been shown to be a critical cytokine in controlling immune activation and indeed deletion of TGF-β signaling in mice leads to development of massive and uncontrolled inflammation, further leading to the untimely death of mice (Kulkarni and others 1993). Importantly, deletion of TGF-β receptors specifically in T cells is sufficient to induce a similar phenotype to systemic Tgfb1 null mice (134), demonstrating the crucial role of TGF-β in regulating T cell functions (Chen and Ten Dijke 2016).

Importantly, our group demonstrated in a seminal article that TGF-β was the crucial inducer of Treg (Chen and others 2003). Quite interestingly, it seems that the TGF-β and IFN-γ signaling pathways regulate each other. It was reported early on that IFN-γ, in a cell line, was able to inhibit the TGF-β signaling pathway. This occurs by JAK1-STAT1 signaling, leading to the induction of the antagonistic SMAD7, therefore leading to the repression of SMAD3 activation (Ulloa and others 1999) (Fig. 1). The opposite is also true since it has been reported that TGF-β, in T cells and NK cells for instance, is able to inhibit T-bet and IFN-γ in a SMAD2/3/4-dependent manner (Yu and others 2006){Li, 2008 #84}. Follow-up work also revealed that TGF-β could impair the generation of Th1 cells through an indirect mechanism.

TGF-β is also repressing the expression of IFN-γ in NK cells, which eventually also represses the generation of Th1 cells in the context of Leishmania infection (Laouar and others 2005). Moreover, TGF-β can also inhibit IFN-γ induction of STAT1 phosphorylation in a mitogen-activated protein kinase kinase /extracellular signal-regulated kinase (MEK/ERK)-dependent manner, leading to the inhibition of IFN-γ-responsive genes in Th1 cells (Park and others 2007).

The many discoveries of Dr. Young and his laboratory demonstrate the crucial role of IFN-γ during immune responses and notably in T cell-mediated immunity. His work has also provided insightful guidance for our laboratory in establishing the role of TGF-β during T cell-mediated immunity, how it regulates the balance between Treg and Th1 cell and how it impacts the development of immune-mediated pathologies. We notably demonstrated that TGF-β, while inducing Treg cells, is also capable of suppressing Th1 generation by inducing their anergy. Of importance, we further demonstrated that TGF-β affects the production of IFN-γ in other cells than CD4 T cells. Indeed, deletion of TGF-βRI in T cells leads to an increased production of IFN-γ in both conventional CD4 and CD8αβ T cells and unconventional TCRβ-CD8αα intraepithelial lymphocytes (Wu and others 2020){Konkel, 2011 #285}.

Intriguingly, when TGF-βRI is deleted on CD4 T cells, it results in increased production of IFN-γ and a resistance to Treg suppression (Tu and others 2018). Another way for TGF-β to control IFN-γ production is through its ability to generate Tregs, which will suppress the generation of Th1 cells and their production of IFN-γ (Chen and others 2003). Activation of TGF-β from its latent form is also a crucial regulator of Treg generation and Th1 suppression. For example, D-mannose, the C-2 epimer of glucose, is able to activate LTGF-β in an integrin αvβ8 and ROS-dependent manner, leading to an increased generation of Treg cells and the suppression of IFN-γ production in T cells. This shifted balance between Treg and Th1 induced by mannose is able to dramatically decrease the frequency of IFN-γ-producing CD4 and CD8 T cells, which protects NOD mice from developing diabetes (Zhang and others 2017).

Finally, our group demonstrated that during efferocytosis (phagocytosis of apoptotic cells by macrophages), high levels of TGF-β were produced, promoting the generation of Treg and decreasing the IFN-γ responses (Perruche and others 2008, 2009; Kasagi and others 2014; Bonnefoy and others 2018; Chen and others 2019; Martin-Rodriguez and others 2021).

Concluding Remarks

The past 3 decades have seen extensive discoveries in the field of immunology made by many important investigators. Dr. Howard Young, in addition to his generous mentoring skills, made several seminal discoveries in the field of immunology and more specifically in the field of IFN-γ biology. His group helped decipher the molecular regulation of IFN-γ in several immune cells, including NK and T cells, as well as its role in the development of autoimmune diseases. His work will have a continuing influence on our studies (among others) in the field of T cell biology and how TGF-β and IFN-γ influence each other during the development of the immune response.

Acknowledgments

This work is supported by the Intramural Research Program of NIH, NIDCR. We would like to thank Teresa Greenwell-Wilde for her critical reading of our article. Dr. W. Chen is especially grateful to Dr. Young for his invaluable mentorship and guidance during Dr. Chen's career development as an immunologist.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research was supported by the Intramural Research Program of NIDCR.

References

  1. Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, Yoshioka Y, Baba T, Konishi I, Mandai, M. 2015. IFN-gamma from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer 112:1501–1509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM, Kay TW, Nicola NA, Hertzog PJ, Metcalf D, Hilton DJ. 1999. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98:597–608. [DOI] [PubMed] [Google Scholar]
  3. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, Kang SP, Shankaran V, Piha-Paul SA, Yearley J, Seiwert TY, Ribas A, Mcclanahan TK. 2017. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 127:2930–2940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bach EA, Szabo SJ, Dighe AS, Ashkenazi A, Aguet M, Murphy KM, Schreiber RD. 1995. Ligand-induced autoregulation of IFN-gamma receptor beta chain expression in T helper cell subsets. Science 270:1215–1218. [DOI] [PubMed] [Google Scholar]
  5. Bae HR, Hodge DL, Yang GX, Leung PSC, Chodisetti SB, Valencia JC, Sanford M, Fenimore JM, Rahman ZSM, Tsuneyama K, Norman GL, Gershwin ME, Young HA. 2018. The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity. Hepatology 67:1408–1419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bae HR, Leung PS, Tsuneyama K, Valencia JC, Hodge DL, Kim S, Back T, Karwan M, Merchant AS, Baba N, Feng D, Park O, Gao B, Yang GX, Gershwin ME, Young HA. 2016. Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. Hepatology 64:1189–1201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bae HR, Leung PSC, Hodge DL, Fenimore JM, Jeon SM, Thovarai V, Dzutsev A, Welcher AA, Boedigheimer M, Damore MA, Choi MS, Fravell RA, Trinchieri G, Gershwin ME, Young HA. 2020. Multi-omics: differential expression of IFN-gamma results in distinctive mechanistic features linking chronic inflammation, gut dysbiosis, and autoimmune diseases. J Autoimmun 111:102436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Baer C, Squadrito ML, Laoui D, Thompson D, Hansen SK, Kiialainen A, Hoves S, Ries CH, Ooi CH, de Palma M. 2016. Suppression of microRNA activity amplifies IFN-gamma-induced macrophage activation and promotes anti-tumour immunity. Nat Cell Biol 18:790–802. [DOI] [PubMed] [Google Scholar]
  9. Balasubramani A, Shibata Y, Crawford GE, Baldwin AS, Hatton RD, Weaver CT. 2010. Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli. Immunity 33:35–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Balomenos D, Rumold R, Theofilopoulos AN. 1998. Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J Clin Invest 101:364–371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Beatty GL, Paterson Y. 2000. IFN-gamma can promote tumor evasion of the immune system in vivo by down-regulating cellular levels of an endogenous tumor antigen. J Immunol 165:5502–5508. [DOI] [PubMed] [Google Scholar]
  12. Benvenuto R, Paroli M, Buttinelli C, Franco A, Barnaba V, Fieschi C, Balsano F. 1992. Tumor necrosis factor-alpha and interferon-gamma synthesis by cerebrospinal fluid-derived T cell clones in multiple sclerosis. Ann N Y Acad Sci 650:341–346. [DOI] [PubMed] [Google Scholar]
  13. Bonnefoy F, Gauthier T, Vallion R, Martin-Rodriguez O, Missey A, Daoui A, Valmary-Degano S, Saas P, Couturier M, Perruche S. 2018. Factors produced by macrophages eliminating apoptotic cells demonstrate pro-resolutive properties and terminate ongoing inflammation. Front Immunol 9:2586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Bream JH, Curiel RE, Yu CR, Egwuagu CE, Grusby MJ, Aune TM, Young HA. 2003. IL-4 synergistically enhances both IL-2- and IL-12-induced IFN-gamma expression in murine NK cells. Blood 102:207–214. [DOI] [PubMed] [Google Scholar]
  15. Bream JH, Hodge DL, Gonsky R, Spolski R, Leonard WJ, Krebs S, Targan S, Morinobu A, O'Shea JJ, Young HA. 2004. A distal region in the interferon-gamma gene is a site of epigenetic remodeling and transcriptional regulation by interleukin-2. J Biol Chem 279:41249–41257. [DOI] [PubMed] [Google Scholar]
  16. Bream JH, Ping A, Zhang X, Winkler C, Young HA. 2002. A single nucleotide polymorphism in the proximal IFN-gamma promoter alters control of gene transcription. Genes Immun 3:165–169. [DOI] [PubMed] [Google Scholar]
  17. Burke JD, Young HA. 2019. IFN-gamma: a cytokine at the right time, is in the right place. Semin Immunol 43:101280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Caretto D, Katzman SD, Villarino AV, Gallo E, Abbas AK. 2010. Cutting edge: the Th1 response inhibits the generation of peripheral regulatory T cells. J Immunol 184:30–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Carroll JM, Crompton T, Seery JP, Watt FM. 1997. Transgenic mice expressing IFN-gamma in the epidermis have eczema, hair hypopigmentation, and hair loss. J Invest Dermatol 108:412–422. [DOI] [PubMed] [Google Scholar]
  20. Carson WE, Ross ME, Baiocchi RA, Marien MJ, Boiani N, Grabstein K, Caligiuri MA. 1995. Endogenous production of interleukin 15 by activated human monocytes is critical for optimal production of interferon-gamma by natural killer cells in vitro. J Clin Invest 96:2578–2582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Castro F, Cardoso AP, Goncalves RM, Serre K, Oliveira MJ. 2018. Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front Immunol 9:847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Chen H, Kasagi S, Chia C, Zhang D, Tu E, Wu R, Zanvit P, Goldberg N, jin W, Chen W. 2019. Extracellular vesicles from apoptotic cells promote TGFbeta production in macrophages and suppress experimental colitis. Sci Rep 9:5875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM. 2003. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Chen W, Ten Dijke P. 2016. Immunoregulation by members of the TGFbeta superfamily. Nat Rev Immunol 16:723–740. [DOI] [PubMed] [Google Scholar]
  25. Cheng J, Myers TG, Levinger C, Kumar P, Kumar J, Goshu BA, Bosque A, Catalfamo M. 2022. IL-27 induces IFN/STAT1-dependent genes and enhances function of TIGIT(+) HIVGag-specific T cells. iScience 25:103588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Chin YE, Kitagawa M, Kuida K, Flavell RA, Fu XY. 1997. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol Cell Biol 17:5328–5337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Chin YE, Kitagawa M, Su WC, You ZH, Iwamoto Y, Fu XY. 1996. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science 272:719–722. [DOI] [PubMed] [Google Scholar]
  28. Chu CQ, Swart D, Alcorn D, Tocker J, Elkon KB. 2007. Interferon-gamma regulates susceptibility to collagen-induced arthritis through suppression of interleukin-17. Arthritis Rheum 56:1145–1151. [DOI] [PubMed] [Google Scholar]
  29. Cippitelli M, Sica A, Viggiano V, Ye J, Ghosh P, Birrer MJ, Young HA. 1995. Negative transcriptional regulation of the interferon-gamma promoter by glucocorticoids and dominant negative mutants of c-Jun. J Biol Chem 270:12548–12556. [DOI] [PubMed] [Google Scholar]
  30. Corbin JG, Kelly D, Rath EM, Baerwald KD, Suzuki K, Popko B. 1996. Targeted CNS expression of interferon-gamma in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development. Mol Cell Neurosci 7:354–370. [DOI] [PubMed] [Google Scholar]
  31. Corthay A, Skovseth DK, Lundin KU, Rosjo E, Omholt H, Hofgaard PO, Haraldsen G, Bogen B. 2005. Primary antitumor immune response mediated by CD4+ T cells. Immunity 22:371–383. [DOI] [PubMed] [Google Scholar]
  32. Darwich L, Coma G, Pena R, Bellido R, Blanco EJ, Este JA, Borras FE, Clotet B, Ruiz L, Rosell A, Andreo F, Parkhouse RM, Bofill M. 2009. Secretion of interferon-gamma by human macrophages demonstrated at the single-cell level after costimulation with interleukin (IL)-12 plus IL-18. Immunology 126:386–393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. de Benedetti F, Prencipe G, Bracaglia C, Marasco E, Grom AA. 2021. Targeting interferon-gamma in hyperinflammation: opportunities and challenges. Nat Rev Rheumatol 17:678–691. [DOI] [PubMed] [Google Scholar]
  34. de Weerd NA, Nguyen T. 2012. The interferons and their receptors—distribution and regulation. Immunol Cell Biol 90:483–491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Derynck R, Budi EH. 2019. Specificity, versatility, and control of TGF-beta family signaling. Sci Signal 12:eaav5183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Dighe AS, Richards E, Old LJ, Schreiber RD. 1994. Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity 1:447–456. [DOI] [PubMed] [Google Scholar]
  37. Dinarello CA. 2007. Historical insights into cytokines. Eur J Immunol 37(Suppl. 1):S34–S45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Dinarello CA, Novick D, Kim S, Kaplanski G. 2013. Interleukin-18 and IL-18 binding protein. Front Immunol 4:289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Domingues HS, Mues M, Lassmann H, Wekerle H, Krishnamoorthy G. 2010. Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. PLoS One 5:e15531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A. 1997. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387:921–924. [DOI] [PubMed] [Google Scholar]
  41. Farrar WL, Birchenall-Sparks MC, Young HB. 1986. Interleukin 2 induction of interferon-gamma mRNA synthesis. J Immunol 137:3836–3840. [PubMed] [Google Scholar]
  42. Fenimore J, Howard AY. 2016. Regulation of IFN-gamma expression. Adv Exp Med Biol 941:1–19. [DOI] [PubMed] [Google Scholar]
  43. Ferber IA, Lee HJ, Zonin F, Heath V, Mui A, Arai N, O'garra A. 1999. GATA-3 significantly downregulates IFN-gamma production from developing Th1 cells in addition to inducing IL-4 and IL-5 levels. Clin Immunol 91:134–144. [DOI] [PubMed] [Google Scholar]
  44. Flaishon L, Hershkoviz R, Lantner F, Lider O, Alon R, Levo Y, Flavell RA, Shachar I. 2000. Autocrine secretion of interferon gamma negatively regulates homing of immature B cells. J Exp Med 192:1381–1388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Fulda S, Debatin KM. 2002. IFNgamma sensitizes for apoptosis by upregulating caspase-8 expression through the Stat1 pathway. Oncogene 21:2295–2308. [DOI] [PubMed] [Google Scholar]
  46. Gajewski TF, Fitch FW. 1988. Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol 140:4245–4252. [PubMed] [Google Scholar]
  47. Gao J, Shi LZ, Zhao H, Chen J, Xiong L, He Q, Chen T, Roszik J, Bernatchez C, Woodman SE, Chen PL, Hwu P, Allison JP, Futreal A, Wargo JA, Sharma P. 2016. Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167:397..e9–404.e9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Gao Y, Yang W, Pan M, Scully E, Girardi M, Augenlicht LH, Craft J, Yin Z. 2003. Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med 198:433–442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Gauthier T, Chen W. 2022. Modulation of macrophage immunometabolism: a new approach to fight infections. Front Immunol 13:780839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Greenlund AC, Farrar MA, Viviano BL, Schreiber RD. 1994. Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J 13:1591–1600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Haabeth OA, Lorvik KB, Hammarstrom C, Donaldson IM, Haraldsen G, Bogen B, Corthay A. 2011. Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer. Nat Commun 2:240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Hall AO, Silver JS, Hunter CA. 2012. The immunobiology of IL-27. Adv Immunol 115:1–44. [DOI] [PubMed] [Google Scholar]
  53. Herr F, Lemoine R, Gouilleux F, Meley D, Kazma I, Heraud A, Velge-Roussel F, Baron C, Lebranchu Y. 2014. IL-2 phosphorylates STAT5 to drive IFN-gamma production and activation of human dendritic cells. J Immunol 192:5660–5670. [DOI] [PubMed] [Google Scholar]
  54. Higgs BW, Morehouse CA, Streicher K, Brohawn PZ, Pilataxi F, Gupta A, Ranade K. 2018. Interferon gamma messenger RNA signature in tumor biopsies predicts outcomes in patients with non-small cell lung carcinoma or urothelial cancer treated with durvalumab. Clin Cancer Res 24:3857–3866. [DOI] [PubMed] [Google Scholar]
  55. Hilliard BA, Mason N, Xu L, Sun J, Lamhamedi-Cherradi SE, Liou HC, Hunter C, Chen YH. 2002. Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation. J Clin Invest 110:843–850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Hirsch RL, Panitch HS, Johnson KP. 1985. Lymphocytes from multiple sclerosis patients produce elevated levels of gamma interferon in vitro. J Clin Immunol 5:386–389. [DOI] [PubMed] [Google Scholar]
  57. Hodge DL, Berthet C, Coppola V, Kastenmuller W, Buschman MD, Schaughency PM, Shirota H, Scarzello AJ, Subleski JJ, Anver MR, Ortaldo JR, Lin F, Reynolds DA, Sanford ME, Kaldis P, Tessarollo L, Klinman DM, Young HA. 2014. IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice. J Autoimmun 53:33–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Hodge DL, Martinez A, Julias JG, Taylor LS, Young HA. 2002. Regulation of nuclear gamma interferon gene expression by interleukin 12 (IL-12) and IL-2 represents a novel form of posttranscriptional control. Mol Cell Biol 22:1742–1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Hu X, Ivashkiv LB. 2009. Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity 31:539–550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Jacob CO, van der Meide PH, Mcdevitt HO. 1987. In vivo treatment of (NZB X NZW)F1 lupus-like nephritis with monoclonal antibody to gamma interferon. J Exp Med 166:798–803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Jager A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK. 2009. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 183:7169–7177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Jenner RG, Townsend MJ, Jackson I, Sun K, Bouwman RD, Young RA, Glimcher LH, Lord GM. 2009. The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proc Natl Acad Sci U S A 106:17876–17881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Jorgovanovic D, Song M, Wang L, Zhang Y. 2020. Roles of IFN-gamma in tumor progression and regression: a review. Biomark Res 8:49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Kalina U, Kauschat D, Koyama N, Nuernberger H, Ballas K, Koschmieder S, Bug G, Hofmann WK, Hoelzer D, Ottmann OG. 2000. IL-18 activates STAT3 in the natural killer cell line 92, augments cytotoxic activity, and mediates IFN-gamma production by the stress kinase p38 and by the extracellular regulated kinases p44erk-1 and p42erk-21. J Immunol 165:1307–1313. [DOI] [PubMed] [Google Scholar]
  65. Kamizono S, Hanada T, Yasukawa H, Minoguchi S, Kato R, Minoguchi M, Hattori K, Hatakeyama S, Yada M, Morita S, Kitamura T, Kato H, Nakayama K, Yoshimura A. 2001. The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2. J Biol Chem 276:12530–12538. [DOI] [PubMed] [Google Scholar]
  66. Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD. 1998. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A 95:7556–7561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Karachaliou N, Gonzalez-Cao M, Crespo G, Drozdowskyj A, Aldeguer E, Gimenez-Capitan A, Teixido C, Molina-Vila MA, Viteri S, de Los Llanos Gil M, Algarra SM, Perez-Ruiz E, Marquez-Rodas I, Rodriguez-Abreu D, Blanco R, Puertolas T, Royo MA, Rosell R. 2018. Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients. Ther Adv Med Oncol 10:1758834017749748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Kasagi S, Zhang P, Che L, Abbatiello B, Maruyama T, Nakatsukasa H, Zanvit P, Jin W, Konkel JE, Chen W. 2014. In vivo-generated antigen-specific regulatory T cells treat autoimmunity without compromising antibacterial immune response. Sci Transl Med 6:241ra78. [DOI] [PubMed] [Google Scholar]
  69. Kasahara T, Hooks JJ, Dougherty SF, Oppenheim JJ. 1983. Interleukin 2-mediated immune interferon (IFN-gamma) production by human T cells and T cell subsets. J Immunol 130:1784–1789. [PubMed] [Google Scholar]
  70. Katz JD, Benoist C, Mathis D. 1995. T helper cell subsets in insulin-dependent diabetes. Science 268:1185–1188. [DOI] [PubMed] [Google Scholar]
  71. Kelchtermans H, Schurgers E, Geboes L, Mitera T, van Damme J, van Snick J, Uyttenhove C, Matthys P. 2009. Effector mechanisms of interleukin-17 in collagen-induced arthritis in the absence of interferon-gamma and counteraction by interferon-gamma. Arthritis Res Ther 11:R122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Kiani A, Garcia-Cozar FJ, Habermann I, Laforsch S, Aebischer T, Ehninger G, Rao A. 2001. Regulation of interferon-gamma gene expression by nuclear factor of activated T cells. Blood 98:1480–1488. [DOI] [PubMed] [Google Scholar]
  73. Kling JC, Jordan MA, Pitt LA, Meiners J, Thanh-Tran T, Tran LS, Nguyen TTK, Mittal D, Villani R, Steptoe RJ, Khosrotehrani K, Berzins SP, Baxter AG, Godfrey DI, Blumenthal A. 2018. Temporal regulation of natural killer T cell interferon gamma responses by beta-catenin-dependent and -independent Wnt signaling. Front Immunol 9:483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G. 1989. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 170:827–845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Kojima H, Aizawa Y, Yanai Y, Nagaoka K, Takeuchi M, Ohta T, Ikegami H, Ikeda M, Kurimoto M. 1999. An essential role for NF-kappa B in IL-18-induced IFN-gamma expression in KG-1 cells. J Immunol 162:5063–5069. [PubMed] [Google Scholar]
  76. Krakowski M, Owens T. 1996. Interferon-gamma confers resistance to experimental allergic encephalomyelitis. Eur J Immunol 26:1641–1646. [DOI] [PubMed] [Google Scholar]
  77. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S. 1993. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A 90:770–774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Laouar Y, Sutterwala FS, Gorelik L, Flavell RA. 2005. Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. Nat Immunol 6:600–607. [DOI] [PubMed] [Google Scholar]
  79. Lees JR. 2015. Interferon gamma in autoimmunity: a complicated player on a complex stage. Cytokine 74:18–26. [DOI] [PubMed] [Google Scholar]
  80. Lees JR, Golumbek PT, Sim J, Dorsey D, Russell JH. 2008. Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis. J Exp Med 205:2633–2642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Lin FC, Karwan M, Saleh B, Hodge DL, Chan T, Boelte KC, Keller JR, Young HA. 2014. IFN-gamma causes aplastic anemia by altering hematopoietic stem/progenitor cell composition and disrupting lineage differentiation. Blood 124:3699–3708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Liu F, Hu X, Zimmerman M, Waller JL, Wu P, Hayes-Jordan A, Lev D, Liu K. 2011. TNFalpha cooperates with IFN-gamma to repress Bcl-xL expression to sensitize metastatic colon carcinoma cells to TRAIL-mediated apoptosis. PLoS One 6:e16241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JR, Raine CS, Heller R, Steinman L. 2002. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8:500–508. [DOI] [PubMed] [Google Scholar]
  84. Lopez-Bravo M, Minguito de la Escalera M, Dominguez PM, Gonzalez-Cintado L, del Fresno C, Martin P, Martinez del Hoyo G, Ardavin C. 2013. IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte-derived dendritic cell differentiation through histone hypoacetylation. J Allergy Clin Immunol 132:1409–1419. [DOI] [PubMed] [Google Scholar]
  85. Lublin FD, Knobler RL, Kalman B, Goldhaber M, Marini J, Perrault M, D'Imperio C, Joseph J, Alkan SS, Korngold R. 1993. Monoclonal anti-gamma interferon antibodies enhance experimental allergic encephalomyelitis. Autoimmunity 16:267–274. [DOI] [PubMed] [Google Scholar]
  86. Luzina IG, Keegan AD, Heller NM, Rook GA, Shea-Donohue T, Atamas SP. 2012. Regulation of inflammation by interleukin-4: a review of “alternatives.” J Leukoc Biol 92:753–764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Martin-Rodriguez O, Gauthier T, Bonnefoy F, Couturier M, Daoui A, Chague C, Valmary-Degano S, Gay C, Saas P, Perruche S. 2021. Pro-resolving factors released by macrophages after efferocytosis promote mucosal wound healing in inflammatory bowel disease. Front Immunol 12:754475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Matikainen S, Paananen A, Miettinen M, Kurimoto M, Timonen T, Julkunen I, Sareneva T. 2001. IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12. Eur J Immunol 31:2236–2245. [PubMed] [Google Scholar]
  89. Matsushita H, Hosoi A, Ueha S, Abe J, Fujieda N, Tomura M, Maekawa R, Matsushima K, Ohara O, Kakimi K. 2015. Cytotoxic T lymphocytes block tumor growth both by lytic activity and IFNgamma-dependent cell-cycle arrest. Cancer Immunol Res 3:26–36. [DOI] [PubMed] [Google Scholar]
  90. Matthys P, Vermeire K, Mitera T, Heremans H, Huang S, Schols D, de Wolf-Peeters C, Billiau A. 1999. Enhanced autoimmune arthritis in IFN-gamma receptor-deficient mice is conditioned by mycobacteria in Freund's adjuvant and by increased expansion of Mac-1+ myeloid cells. J Immunol 163:3503–3510. [PubMed] [Google Scholar]
  91. Mauritz NJ, Holmdahl R, Jonsson R, van der Meide PH, Scheynius A, Klareskog L. 1988. Treatment with gamma-interferon triggers the onset of collagen arthritis in mice. Arthritis Rheum 31:1297–1304. [DOI] [PubMed] [Google Scholar]
  92. Mortara L, Balza E, Bruno A, Poggi A, Orecchia P, Carnemolla B. 2018. Anti-cancer therapies employing IL-2 cytokine tumor targeting: contribution of innate, adaptive and immunosuppressive cells in the anti-tumor efficacy. Front Immunol 9:2905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. 1986. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357. [PubMed] [Google Scholar]
  94. Murphy KM, Reiner SL. 2002. The lineage decisions of helper T cells. Nat Rev Immunol 2:933–944. [DOI] [PubMed] [Google Scholar]
  95. Nakajima C, Uekusa Y, Iwasaki M, Yamaguchi N, Mukai T, Gao P, Tomura M, Ono S, Tsujimura T, Fujiwara H, Hamaoka T. 2001. A role of interferon-gamma (IFN-gamma) in tumor immunity: T cells with the capacity to reject tumor cells are generated but fail to migrate to tumor sites in IFN-gamma-deficient mice. Cancer Res 61:3399–3405. [PubMed] [Google Scholar]
  96. Nakajima H, Takamori H, Hiyama Y, Tsukada W. 1990. The effect of treatment with interferon-gamma on type II collagen-induced arthritis. Clin Exp Immunol 81:441–445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Naylor SL, Gray PW, Lalley PA. 1984. Mouse immune interferon (IFN-gamma) gene is on chromosome 10. Somat Cell Mol Genet 10:531–534. [DOI] [PubMed] [Google Scholar]
  98. Naylor SL, Sakaguchi AY, Shows TB, Law ML, Goeddel DV, Gray PW. 1983. Human immune interferon gene is located on chromosome 12. J Exp Med 157:1020–1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Novelli F, Bernabei P, Ozmen L, Rigamonti L, Allione A, Pestka S, Garotta G, Forni G. 1996. Switching on of the proliferation or apoptosis of activated human T lymphocytes by IFN-gamma is correlated with the differential expression of the alpha- and beta-chains of its receptor. J Immunol 157:1935–1943. [PubMed] [Google Scholar]
  100. O'Shea JJ, Murray PJ. 2008. Cytokine signaling modules in inflammatory responses. Immunity 28:477–487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Ohteki T, Fukao T, Suzue K, Maki C, Ito M, Nakamura M, Koyasu S. 1999. Interleukin 12-dependent interferon gamma production by CD8alpha+ lymphoid dendritic cells. J Exp Med 189:1981–1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Olalekan SA, Cao Y, Hamel KM, Finnegan A. 2015. B cells expressing IFN-gamma suppress Treg-cell differentiation and promote autoimmune experimental arthritis. Eur J Immunol 45:988–998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Oriss TB, McCarthy SA, Morel BF, Campana MA, Morel PA. 1997. Crossregulation between T helper cell (Th)1 and Th2: inhibition of Th2 proliferation by IFN-gamma involves interference with IL-1. J Immunol 158:3666–3672. [PubMed] [Google Scholar]
  104. Pang Y, Norihisa Y, Benjamin D, Kantor RR, Young HA. 1992. Interferon-gamma gene expression in human B-cell lines: induction by interleukin-2, protein kinase C activators, and possible effect of hypomethylation on gene regulation. Blood 80:724–732. [PubMed] [Google Scholar]
  105. Panitch HS, Hirsch RL, Schindler J, Johnson KP. 1987. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 37:1097–1102. [DOI] [PubMed] [Google Scholar]
  106. Park IK, Letterio JJ, Gorham JD. 2007. TGF-beta 1 inhibition of IFN-gamma-induced signaling and Th1 gene expression in CD4+ T cells is Smad3 independent but MAP kinase dependent. Mol Immunol 44:3283–3290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Pernis A, Gupta S, Gollob KJ, Garfein E, Coffman RL, Schindler C, Rothman P. 1995. Lack of interferon gamma receptor beta chain and the prevention of interferon gamma signaling in TH1 cells. Science 269:245–247. [DOI] [PubMed] [Google Scholar]
  108. Perruche S, Zhang P, Liu Y, Saas P, Bluestone JA, Chen W. 2008. CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells. Nat Med 14:528–535. [DOI] [PubMed] [Google Scholar]
  109. Perruche S, Zhang P, Maruyama T, Bluestone JA, Saas P, Chen W. 2009. Lethal effect of CD3-specific antibody in mice deficient in TGF-beta1 by uncontrolled flu-like syndrome. J Immunol 183:953–961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, Hibbert L, Churakova T, Travis M, Vaisberg E, Blumenschein WM, Mattson JD, Wagner JL, To W, Zurawski S, McClanahan TK, Gorman DM, Bazan JF, de Waal Malefyt R, Rennick D, Kastelein RA. 2002. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16:779–790. [DOI] [PubMed] [Google Scholar]
  111. Pitroda SP, Wakim BT, Sood RF, Beveridge MG, Beckett MA, Macdermed DM, Weichselbaum RR, Khodarev NN. 2009. STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect. BMC Med 7:68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Qiao Y, Giannopoulou EG, Chan CH, Park SH, Gong S, Chen J, Hu X, Elemento O, Ivashkiv LB. 2013. Synergistic activation of inflammatory cytokine genes by interferon-gamma-induced chromatin remodeling and toll-like receptor signaling. Immunity 39:454–469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Ramana CV, Grammatikakis N, Chernov M, Nguyen H, Goh KC, Williams BR, Stark GR. 2000. Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways. EMBO J 19:263–272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Robertson IB, Rifkin DB. 2016. Regulation of the bioavailability of TGF-beta and TGF-beta-related proteins. Cold Spring Harb Perspect Biol 8:a021907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Samten B, Townsend JC, Weis SE, Bhoumik A, Klucar P, Shams H, Barnes PF. 2008. CREB, ATF, and AP-1 transcription factors regulate IFN-gamma secretion by human T cells in response to mycobacterial antigen. J Immunol 181:2056–2064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Sarvetnick N, Shizuru J, Liggitt D, Martin L, Mcintyre B, Gregory A, Parslow T, Stewart T. 1990. Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma. Nature 346:844–847. [DOI] [PubMed] [Google Scholar]
  117. Savan R, Ravichandran S, Collins JR, Sakai M, Young HA. 2009. Structural conservation of interferon gamma among vertebrates. Cytokine Growth Factor Rev 20:115–124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  118. Seery JP, Carroll JM, Cattell V, Watt FM. 1997. Antinuclear autoantibodies and lupus nephritis in transgenic mice expressing interferon gamma in the epidermis. J Exp Med 186:1451–1459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. 2001. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107–1111. [DOI] [PubMed] [Google Scholar]
  120. Shimozato O, Ortaldo JR, Komschlies KL, Young HA. 2002. Impaired NK cell development in an IFN-gamma transgenic mouse: aberrantly expressed IFN-gamma enhances hematopoietic stem cell apoptosis and affects NK cell differentiation. J Immunol 168:1746–1752. [DOI] [PubMed] [Google Scholar]
  121. Sica A, Dorman L, Viggiano V, Cippitelli M, Ghosh P, Rice N, Young HA. 1997. Interaction of NF-kappaB and NFAT with the interferon-gamma promoter. J Biol Chem 272:30412–30420. [DOI] [PubMed] [Google Scholar]
  122. Sica A, Tan TH, Rice N, Kretzschmar M, Ghosh P, Young HA. 1992. The c-rel protooncogene product c-Rel but not NF-kappa B binds to the intronic region of the human interferon-gamma gene at a site related to an interferon-stimulable response element. Proc Natl Acad Sci U S A 89:1740–1744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  123. Song M, Ping Y, Zhang K, Yang L, Li F, Zhang C, Cheng S, Yue D, Maimela NR, Qu J, Liu S, Sun T, Li Z, Xia J, Zhang B, Wang L, Zhang Y. 2019. Low-dose IFNgamma induces tumor cell stemness in tumor microenvironment of non-small cell lung cancer. Cancer Res 79:3737–3748. [DOI] [PubMed] [Google Scholar]
  124. Su X, Yu Y, Zhong Y, Giannopoulou EG, Hu X, Liu H, Cross JR, Ratsch G, RICE, CM, Ivashkiv LB. 2015. Interferon-gamma regulates cellular metabolism and mRNA translation to potentiate macrophage activation. Nat Immunol 16:838–849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  125. Takeda K, Nakayama M, Hayakawa Y, Kojima Y, Ikeda H, Imai N, Ogasawara K, Okumura K, Thomas DM, Smyth MJ. 2017. IFN-gamma is required for cytotoxic T cell-dependent cancer genome immunoediting. Nat Commun 8:14607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. Takeda K, Smyth MJ, Cretney E, Hayakawa Y, Kayagaki N, Yagita H, Okumura K. 2002. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 195:161–169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  127. Taniguchi K, Petersson M, Hoglund P, Kiessling R, Klein G, Karre K. 1987. Interferon gamma induces lung colonization by intravenously inoculated B16 melanoma cells in parallel with enhanced expression of class I major histocompatibility complex antigens. Proc Natl Acad Sci U S A 84:3405–3409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  128. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N. 2001. IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 19:623–655. [DOI] [PubMed] [Google Scholar]
  129. Thapa RJ, Basagoudanavar SH, Nogusa S, Irrinki K, Mallilankaraman K, Slifker MJ, Beg AA, Madesh M, Balachandran S. 2011. NF-kappaB protects cells from gamma interferon-induced RIP1-dependent necroptosis. Mol Cell Biol 31:2934–2946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  130. Trinchieri G. 2003. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146. [DOI] [PubMed] [Google Scholar]
  131. Tu E, Chia CPZ, Chen W, Zhang D, Park SA, Jin W, Wang D, Alegre ML, Zhang YE, Sun L, Chen W. 2018. T cell receptor-regulated TGF-beta type i receptor expression determines T cell quiescence and activation. Immunity 48:745..e6–759.e6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  132. Ulloa L, Doody J, Massague J. 1999. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 397:710–713. [DOI] [PubMed] [Google Scholar]
  133. van Acker HH, Anguille S, de Reu H, Berneman ZN, Smits EL, van Tendeloo VF. 2018. Interleukin-15-cultured dendritic cells enhance anti-tumor gamma delta T cell functions through IL-15 secretion. Front Immunol 9:658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  134. Verheul TCJ, van Hijfte L, Perenthaler E, Barakat TS. 2020. The why of YY1: mechanisms of transcriptional regulation by Yin Yang 1. Front Cell Dev Biol 8:592164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  135. Vermeire K, Heremans H, Vandeputte M, Huang S, Billiau A, Matthys P. 1997. Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice. J Immunol 158:5507–5513. [PubMed] [Google Scholar]
  136. Wheelock EF. 1965. Interferon-like virus-inhibitor induced in human leukocytes by phytohemagglutinin. Science 149:310–311. [PubMed] [Google Scholar]
  137. Wu R, Zhang D, Zanvit P, Jin W, Wang H, Chen W. 2020. Identification and regulation of TCRalphabeta(+)CD8alphaalpha(+) intraepithelial lymphocytes in murine oral mucosa. Front Immunol 11:1702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  138. Xu X, Fu XY, Plate J, Chong AS. 1998. IFN-gamma induces cell growth inhibition by Fas-mediated apoptosis: requirement of STAT1 protein for up-regulation of Fas and FasL expression. Cancer Res 58:2832–2837. [PubMed] [Google Scholar]
  139. Yagi R, Junttila IS, Wei G, Urban JF, JR., Zhao K, Paul WE, Zhu J.. 2010. The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-gamma. Immunity 32:507–517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  140. Ye J, Cippitelli M, Dorman L, Ortaldo JR, Young HA. 1996. The nuclear factor YY1 suppresses the human gamma interferon promoter through two mechanisms: inhibition of AP1 binding and activation of a silencer element. Mol Cell Biol 16:4744–4753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  141. Ye J, Ghosh P, Cippitelli M, Subleski J, Hardy KJ, Ortaldo JR, Young HA. 1994. Characterization of a silencer regulatory element in the human interferon-gamma promoter. J Biol Chem 269:25728–25734. [PubMed] [Google Scholar]
  142. Ye J, Ortaldo JR, Conlon K, Winkler-Pickett R, Young HA. 1995. Cellular and molecular mechanisms of IFN-gamma production induced by IL-2 and IL-12 in a human NK cell line. J Leukoc Biol 58:225–233. [DOI] [PubMed] [Google Scholar]
  143. Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, Akira S, Nakanishi K. 1998. IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J Immunol 161:3400–3407. [PubMed] [Google Scholar]
  144. Young HA, Klinman DM, Reynolds DA, Grzegorzewski KJ, Nii A, Ward JM, Winkler-Pickett RT, Ortaldo JR, Kenny JJ, Komschlies KL. 1997. Bone marrow and thymus expression of interferon-gamma results in severe B-cell lineage reduction, T-cell lineage alterations, and hematopoietic progenitor deficiencies. Blood 89:583–595. [PubMed] [Google Scholar]
  145. Yu J, Wei M, Becknell B, Trotta R, Liu S, Boyd Z, Jaung MS, Blaser BW, Sun J, Benson DM Jr., Mao H, Yokohama A, Bhatt D, Shen L, Davuluri R, Weinstein M, Marcucci G, Caligiuri MA.. 2006. Pro- and antiinflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity 24:575–590. [DOI] [PubMed] [Google Scholar]
  146. Zhang D, Chia C, Jiao X, Jin W, Kasagi S, Wu R, Konkel JE, Nakatsukasa H, Zanvit P, Goldberg N, Chen Q, Sun L, Chen ZJ, Chen W. 2017. D-mannose induces regulatory T cells and suppresses immunopathology. Nat Med 23:1036–1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  147. Zhang YE. 2017. Non-Smad signaling pathways of the TGF-beta family. Cold Spring Harb Perspect Biol 9:a022129. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Interferon & Cytokine Research are provided here courtesy of Mary Ann Liebert, Inc.

RESOURCES