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The function of type I interferons in antimicrobial immunity
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The function of type I interferons in antimicrobial immunity Christian Bogdan Type I interferons (IFN-α and IFN-β) were originally described as potent antiviral substances, which are produced upon infection of animal cells with viruses. Despite a large body of literature that has accumulated during the past 25 years, their regulatory function in the immune system is still much less appreciated. Recent studies have highlighted the production of type I IFNs, their function in the immune response to infectious agents and the target cells of these interferons. Type I IFNs clearly affect the release of proinflammatory cytokines or nitric oxide by dendritic cells and macrophages, the capacity of type II interferon (IFN-γ) to activate phagocytes, the differentiation of T helper cells and the innate control of non-viral pathogens.
the interferon-regulatory factor 1 (IRF-1) were required whereas Jak2 was dispensable [7–13].
Current Opinion in Immunology 2000, 12:419–424
The potent activity of IFN-α/β against viral infections is based firstly on the expression of IFN-inducible protective genes (e.g. encoding 2′–5′oligoadenylate synthetase, doublestranded RNA-activated protein kinase, guanylate-binding protein and MxA protein) that confer cellular resistance, inhibit viral replication and impede viral dissemination and secondly on certain immunomodulatory effects [14–16]. Various other functions of IFN-α/β in the immune system — such as the modulation of antibody production, the enhancement of T cell and NK cell cytotoxicity, the inhibition of lymphocyte proliferation, the inhibition of suppressor T cells and the preferential differentiation of T helper cells into Th1 cells — have been recognized for quite some time and reviewed previously [17]. The present overview focuses on more recent data that are relevant to our understanding of the function of IFN-α/β in antimicrobial immunity.
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α/β β and its regulation Production of IFN-α
Addresses Institute of Clinical Microbiology, Immunology and Hygiene, University of Erlangen, Wasserturmstrasse 3, D-91054 Erlangen, Germany; e-mail: [email protected]
Abbreviations LPS lipopolysaccharide MCMV mouse cytomegalovirus NOS2 type 2 nitric oxide synthase Stat1 signal transducer and activator of transcription 1
Introduction Type I interferons form an ancient family of cytokines that comprises IFN-α, IFN-β, IFN-δ, IFN-ω and IFN-τ. They are coded by intronless genes and are widely distributed amongst vertebrates. Whereas IFN-β is coded by a single gene in primates and rodents, more than 10 and 15 different subtypes of IFN-α have been found in mice and man, respectively. IFN-δ has been described in the pig, IFN-τ in cattle and sheep, and IFN-ω in cattle and humans [1]. Although all type I IFNs apparently exhibit antiviral and antiproliferative activities and thereby help to control viral infections and tumors [2–6], the role of type I IFNs in the immune system has been characterized in detail only for IFN-α and IFN-β (in the following text, these are collectively termed IFN-α/β). The action of IFN-α/β on target cells such as fibroblasts, T cells, macrophages or dendritic cells is mediated by the type I IFN receptor (a member of the class II helical cytokine receptor family) that consists of two subunits, the α-chain (IFNAR-1) and the β-chain (IFNAR-2). The latter has long (βL) and short (βS) forms. Mutational analyses and studies in gene-deficient mice revealed that for the induction of certain interferon response genes and/or for full (antiviral) activity of IFN-α or IFN-β, both receptor subunits, the Janus kinases Jak1 and Tyk2, signal transducer and activator of transcription 1 (Stat1) and, to some extent,
For a long time macrophages have been known to be a major cellular source of IFN-α/β in the immune system. Several studies have demonstrated a low-level constitutive expression of IFN-α/β already in resting macrophages ([17–19] and references therein). The production of IFNα/β by macrophages is upregulated upon infection with viruses, stimulation with double-stranded RNA or exposure to microbial pathogens (e.g. Chlamydia trachomatis, Escherichia coli, Listeria monocytogenes or Leishmania major) or to microbial products (e.g. lipopolysaccharide [LPS] or bacterial DNA) [20–23,24•]. Other sources of IFN-α/β include fibroblasts, NK cells, T cells, dendritic cells and a group of specialized leukocytes, the plasmacytoid monocytes ([17,25,26,27•,28••] and references therein). Recently, strong evidence was presented that the latter are precursors of dendritic cells. Plasmacytoid monocytes (which have a plasma-cell-like morphology) constitute a rare cell type that differs from monocytes and monocytederived dendritic cells by the absence of myeloid markers (e.g. CD11c, CD13 and CD33) and the production of high amounts of IFN-α/β in human peripheral blood upon infection with viruses or bacteria [26,27•,28••]. The various pro- and anti-inflammatory functions of IFNα/β (see below) necessitate a strict regulation of its production. Cytokines with known macrophage-inhibitory functions (e.g. IL-4 or IL-10) were also shown to suppress the production of IFN-α or IFN-β in mouse or human macrophages [18,29,30]. Apart from cytokines, the production of IFN-α/β is also regulated by inorganic molecules. In resting mouse peritoneal macrophages, constitutively released low levels of NO inhibited the expression of IFN-α4 mRNA and, to a minor extent, of IFN-β mRNA [31•].
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α/β β, IFN-γγ and macrophages IFN-α Macrophages function as host and effector cells for a large number of intracellular pathogens and are subject to the effects of numerous cytokines (including IFN-α/β) that are relevant in antimicrobial immunity. IFN-α/β markedly supports the differentiation of monocytes into dendritic cells with potent antigen-presenting activity, stimulates macrophage antibody-dependent cytotoxicity and positively or negatively regulates the production of various cytokines (e.g. TNF, IL-1, IL-6, IL-8, IL-12 and IL-18) by macrophages [21,32–34]. In addition, autocrine IFN-α/β is required for the enhancement of macrophage phagocytosis by M-CSF and IL-4 [35]. In human monocytes, recombinant IFN-α2b led to the induction of type 2 nitric oxide synthase (NOS2 or iNOS), an important antimicrobial effector pathway. In mouse macrophages, in contrast, exogenous IFN-α/β alone was unable to induce NOS2 but synergistic effects were observed in the presence of LPS or of L. major parasites (reviewed in [36]). Furthermore, autocrine IFN-α/β was essential for the induction of NOS2 by LPS or by viruses and IFN-γ [37,38]. On the other hand, pre-exposure of macrophages to IFN-α/β was shown to counteract several effects of IFN-γ, including the induction of MHC class II molecules, the downregulation of mannose-fucose receptor, the induction of cell death (apoptosis) and the expression of NOS2 ([36,39,40] and references therein). This unexpected heterogeneity of the effects of IFN-α/β on macrophages suggests that IFN-α/β can assume both protective and counter-protective functions during infectious diseases.
α/β β, IL-12, NK cells and T cells IFN-α IL-12, which is produced by macrophages and dendritic cells in response to cytokines and certain microbial stimuli, plays a pivotal role in the control of a large number of intracellular pathogens that is thought to result from its strong activating effects on NK cells and T cells. IFN-α/β has been shown to raise the levels of IL-12 and IL-18 mRNA in human macrophages and to synergize with IL-12 for the activation of NK cells to produce IFN-γ [17,21,41]. Similarly, IFN-α/β upregulated the expression of the IL-12 receptor β2 chain (IL-12Rβ2) in human CD4+ T cells and thereby facilitated their differentiation into IFN-γ-producing Th1 cells in response to IL-12 [42]. Although IFN-γ rather than IFN-α/β promoted the expression of IL-12Rβ2 and the subsequent IL-12-driven development of Th1 cells in naive mouse T cells [43,44], the overall experimental evidence clearly suggests that both IFN-α and IFN-β favor the generation of IFN-γ-producing CD4+ T cells in man and mice ([45–50]; see also Update). On the other hand, however, several studies demonstrated that IFN-α/β is a potent suppressor of the production of IL-12 as was seen in mixed splenic leukocyte populations or in cocultures of naive CD4+CD45RA+ T cells and dendritic cells as antigen-presenting cells [51,52•]. The negative regulatory effect of IFN-α/β was restricted to the induction of IL-12 that is mediated by CD40/CD40-ligand
and was not observed when dendritic cells were stimulated with LPS; IFN-α/β thus appears to interfere with a stimulatory signal elicited by CD40 [52•]. Taken together, these in vitro findings raise the question about the effect that endogenously produced (or therapeutically applied) IFN-α/β might have on the production of IL-12 and/or the development of Th1 cells in vivo. In mice infected with mouse cytomegalovirus (MCMV), neutralization of IFN-α/β or deletion of IFNAR-1 drastically increased the serum levels of IL-12 p40, IL-12 p70 and IFN-γ. Furthermore, during an ongoing MCMV infection, the ability of LPS to induce IL-12 was significantly suppressed but was restored upon treatment with anti-IFN-α/β. Thus, endogenous IFN-α/β can function as an inhibitor of IL-12 production in vivo, even if the IL-12 release is triggered by LPS [51]. It is possible that such a mechanism accounts for the T cell immunosuppression (and the increased susceptibility to intracellular bacteria or parasites) observed in patients with chronic viral infections (e.g. HIV) and a continuous upregulation of IFN-α/β [53]. On the other hand, recent clinical reports demonstrated that in patients who received a Mycobacterium bovis BCG immunotherapy for bladder cancer and in a patient who was suffering from chronic hepatitis C and progressive hepatic alveolar echinococcosis, treatment with recombinant human IFN-α2 led to enhanced Th1 cytokine responses (i.e. IFN-γ and IL-12) in vitro and in vivo [54,55]. These results are clearly preliminary and it is likely that both pro- and antiinflammatory effects occur during IFN-α/β treatment. Apart from governing the differentiation and cytokinesecretion pattern of T cells, IFN-α/β exerts a number of other effects on T cells; the significance of these effects during infectious diseases remains to be analysed. They include the rescue of activated or memory T cells from apoptosis [56•,57•], the induction of proliferation of memory-phenotype CD8+ T cells in the presence of antigen-presenting cells [58], the direct inhibition of proliferation of naive T cells [59,60] and the modulation of the chemokine receptor expression on the T cell surface (reviewed in [61]).
α/β β and infectious diseases IFN-α Viral infections
Studies with mice lacking IFNAR-I, IFN-β or Stat1α, or expressing tissue-specific type-I-IFN transgenes have demonstrated that type I IFNs control infections with a broad spectrum of viruses, including members of the family of poxviruses (vaccinia virus), herpesviridae (herpes simplex virus type 1 and MCMV), orthomyxoviruses (influenza A virus), paramyxoviridae (measles virus), arenaviruses (lymphocytic choriomeningitis virus [LCMV]), rhabdoviridae (vesicular stomatitis virus), picornaviridae (Theiler’s virus) and togaviridae (Semliki forest virus, Sindbis virus and Venezuelan equine encephalitis virus) [16,62–66,67•,68•]. In some of these infections, IFN-α/β was shown not only to directly suppress viral replication but also to specifically protect antigen-presenting cells (marginal zone macrophages
Type I interferons in antimicrobial immunity Bogdan
and dendritic cells) from productive infections with the virus and to prevent a fatal systemic inflammatory response syndrome (characterized by the release of IL-12, IFN-γ, TNF and IL-6) in the host organism [51,67•]. Furthermore, in the LCMV model, evidence was provided for the existence of two alternative pathways (IL-12- or IFN-α/β-dependent) each of which leads to a strong CD8+ T cell response and IFN-γ production and is sufficient to clear the infection in vivo [69••]. Another effector mechanism that is known to control the replication of certain viruses is the production of NO [36]. Although IFN-α/β is able to induce NO in the presence of a (viral) costimulus (see above), NOS2-deficient mice infected with hepatitis B virus were not resistant to the antiviral effects of endogenously produced IFN-α/β. This indicates that, at least in this model, the antiviral activity of IFN-α/β is NOS2-independent [70••]. In mice lacking a functional type I IFN receptor and in mice with an IFN-β gene deletion (but with unaltered IFN-α genes), the course of a vaccinia virus infection was aggravated to a similar degree compared with wild-type mice [7,68•]. This unexpected observation may be caused by the fact that, at least in vitro, the viral induction of IFN-α in fibroblasts (but not in leukocytes) was critically dependent on endogenous IFN-β [68•,71]. Future studies, however, will be necessary in order to clarify the regulatory relationship between the various type I IFNs in vivo. Host-cell-derived cytokines regulate not only the production but also the antiviral function of IFN-α/β. Notable examples of inhibitory factors for this function are firstly IL-8, a chemokine that is typically induced by a wide variety of viruses, and secondly the soluble IFN-α/β receptor ([72,73] and references therein; see also Update). Non-viral infections
Compared with viral infections, the role of type I IFNs for the defense against non-viral pathogens (i.e. bacteria, protozoa, fungi and helminths) has been considerably less well studied. Nevertheless, by now at least four interactions and functional relationships between these pathogens and IFN-α/β have been firmly established. First, treatment of macrophages (or neutrophils) with IFN-α or IFN-β enhanced their antimicrobial activity against C. psittaci, Mycobacterium avium, Toxoplasma gondii, Leishmania spp. or Candida albicans, particularly in the presence of endotoxin (LPS) [40,74–81]. However, it should be mentioned that induction of antimicrobial activity by IFN-α/β was not observed in other studies [82,83]. Second, in macrophages or fibroblasts certain bacteria or protozoa induce the production of IFN-α/β in vitro (see above). Third, IFN-α/β is produced during the immune response against bacterial or protozoan pathogens in vivo [23,84–86]. Fourth, recombinant mouse IFN-β protected mice against an infection with L. monocytogenes [87]; a similar protective effect of type I interferons was also seen in mice infected with Trypanosoma cruzi [88] or with T. gondii [79]. In mice infected with M. avium, the continuous application of IFN-β led
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to a one-log reduction of the bacterial burden in the liver and spleen [81]. In all four models, however, the function of endogenously produced IFN-α/β remains to be identified. In the mouse model of cutaneous leishmaniasis, IFN-α/β was already expressed at day one of infection with L. major in the skin lesion and was indispensable for the early expression of NOS2, the innate production of IFN-γ, the NK cell cytotoxic activity and the initial control of parasite spreading. Despite a severely impaired innate immune response, the neutralization of IFN-α/β four hours prior to and at the time of infection did not prevent the ultimate cure of the infection ([23]; C Bogdan, unpublished data). However, the course of L. major infection has not yet been evaluated under conditions of prolonged neutralization of endogenous IFN-α/β or in mice lacking type I IFN receptor signaling.
Functional differences between different type I IFNs? The existence of so many type I IFN genes raises the question about whether their protein products differ in their functions in the immune system. Although all type I IFNs are thought to signal through the same type I IFN receptor, there is evidence for differential receptor binding and signaling of IFN-α and IFN-β [13]. IFN-α2 and IFN-β were shown to require distinct intracytoplasmic regions of the βL chain to elicit an antiviral response and it was suggested that they differentially activate additional signaling molecules other than members of the Stat pathway ([89] and references therein). In vitro, recombinant IFN-β was much more active in clearing a persistent infection of human myocardial fibroblasts with coxsackievirus B3 than recombinant human IFN-α2 [90]. The virus-induced expression of the different IFN-α genes shows cell-type-dependent variations and appears to be differentially dependent on de novo protein synthesis and on Stat1 activation [91,92], which might be another source for heterogeneity. In vivo the antiviral efficacy of the IFN-α subtypes might indeed vary, as recently seen in MCMV-infected mice that were injected with plasmids expressing IFN-α1, IFN-α4 or IFN-α9. In this study, IFN-α1 turned out to exhibit the strongest antiviral effect but the possibility that the rate of production of each IFN subtype is not equivalent in situ could not be excluded [63].
Conclusions The potent antiviral function of IFN-α/β, which is due to both direct effects (i.e. mediating resistance to viruses) and indirect effects (i.e. immunostimulation), has been well established and has led to the approval of IFN-α for clinical use (e.g. treatment of chronic hepatitis B or C). Until now, the role of type I IFNs in defense against bacteria and parasites has been poorly studied but it is likely to be more complex than in viral infections. Based on the currently available data, protective and counter-protective effects of IFN-α/β can be envisaged because IFN-α/β exerts both agonistic and antagonistic effects on several components of the immune response that are critical for the control of intracellular bacteria or protozoa (e.g. synthesis of NO,
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synthesis of proinflammatory cytokines, macrophage activation by IFN-γ and the differentiation, activation or proliferation of T helper cells). Detailed in vivo analyses in animal models will be required before clinical application of IFN-α/β in non-viral infections can be considered.
Update α/β and T cells IFN-α
Recently, a novel mechanism by which IFN-α might promote and maintain an ongoing Th1 response was described [93]. IFN-α (as well as IL-12) inhibited the production of two chemokines (macrophage-derived chemokine [MDC] and I-309), which predominantly attract Th2 cells.
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α/β and viral infections IFN-α
Hajnicka et al. [94] have shown that the salivary gland extract of the tick, Dermacentor reticulans, inhibits the antiviral activity of purified mouse IFN-α/β. This finding might explain why ticks are efficient vectors of certain arboviruses.
Acknowledgements The author thanks Martin Röllinghoff and Ion Gresser for helpful comments on the manuscript. This research was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 263 A5).
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Pilling D, Akbar AN, Girdlestone J, Orteu CH, Borthwick NJ, Amft N, β mediates Scheel-Toellner D, Buckley CD, Salmon M: Interferon-β stromal cell rescue of T cells from apoptosis. Eur J Immunol 1999, 29:1041-1050. This and the paper by Marrack et al. [56•] define a novel, antiapoptotic effect of IFN-α/β on T cells. The survival signal delivered by IFN-α/β appears to be distinct from its ability to modulate T cell growth (see [58–60]). 58. Tough DF, Borrow P, Sprent J: Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 1996, 272:1947-1950. 59. Sun S, Zhang X, Tough DF, Sprent J: Type I interferon-mediated stimulation of T cells by CpG DNA. J Exp Med 1998, 188:2335-2342. 60. Petricoin EF, Ito S, Williams BL, Audet S, Stancato LF, Gamero A, Clouse K, Grimley P, Weiss A, Beeler J et al.: Antiproliferative action α requires components of T cell-receptor signalling. of interferon-α Nature 1997, 390:629-632. 61. Sallusto F, Lanzavecchia A, Mackay CR: Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunol Today 1998, 19:568-574. 62. Garcia-Sastre A, Durbin RK, Zheng H, Palese P, Gertner R, Levy DE, Durbin JE: The role of interferon in influenza virus tissue tropism. J Virol 1998, 72:8550-8558. 63. Yeow W-S, Lawson CM, Beilharz MW: Antiviral activities of α subtypes in vivo: intramuscular injection individual murine IFN-α of IFN expression constructs reduces cytomegalovirus replication. J Immunol 1998, 160:2932-2939. 64. Noisakran S, Campbell IL, Carr DJJ: Ectopic expression of DNA α1 in the cornea protects mice from herpes encoding IFN-α simplex virus type 1-induced encephalitis. J Immunol 1999, 162:4184-4190. 65. Leib DA, Harrison TE, Laslo KM, Machalek MA, Moorman NJ, Virgin HW: Interferons regulate the phenotype of wildtype and mutant herpes simplex viruses in vivo. J Exp Med 1999, 189:663-672. 66. Mrkic B, Odermatt B, Klein MA, Billeter MA, Pavlovic J, Cattaneo R: Lymphatic dissemination and comparative pathology of
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Ryman KD, Klimstra WB, Nguyen KB, Biron CA, Johnston RE: Alpha/beta interferon protects adult mice from fatal sindbis virus infection and is an important determinant of cell and tissue tropism. J Virol 2000, 74:3366-3378. In mice lacking the type I IFN receptor a subcutaneous infection with Sindbis virus leads to rapid viral replication in cells of the macrophage/dendritic-cell lineage, in the draining lymph node (within 24 hours of infection) and in visceral organs (i.e. within 72 hours in spleen, liver, lung, thymus and kidney). 68. Deonarain R, Alcami A, Alexiou M, Dallman MJ: Impaired antiviral • response and alpha/beta interferon induction in mice lacking beta interferon. J Virol 2000, 74:3404-3409. This study provides direct in vivo evidence for a hierarchy amongst type I IFNs, in which IFN-β is required for the expression of IFN-α. 69. Cousens LP, Peterson R, Hsu S, Dorner A, Altman JD, Ahmed R, α/β β- and interleukin-12•• Biron CA: Two roads diverged: interferon-α mediated pathways in promoting T cell interferon-γγ responses during viral infection. J Exp Med 1999, 189:1315-1327. Using the LCMV infection model, this paper shows that in the presence of endogenous IFN-α/β the CD8+ T cell IFN-γ response is independent of IL-12 whereas in the absence of IFN-α/β functions (due to a deletion of the IFNAR-1) endogenous IL-12 constituted an alternative pathway leading to the expression of IFN-γ. 70. Guidotti LG, McClary H, Moorhead Loudis J, Chisari FV: Nitric oxide •• inhibits hepatitis B virus replication in the livers of transgenic mice. J Exp Med 2000, 191:1247-1252. This is the first study to dissect the direct, NO-independent antiviral effects of IFNs from indirect, NO-dependent effects. Whereas the antiviral effect of IFN-γ is mainly mediated by the induction of NOS2, IFN-α/β is able to exert a direct, NO-independent effect on hepatitis B virus replication. 71. Erlandsson L, Blumenthal R, Eloranta M-L, Engel H, Alm G, Weiss S, β is required for interferon-α α production Leanderson T: Interferon-β in mouse fibroblasts. Curr Biol 1998, 8:223-226. 72. Khabar KSA, Al-Zoghaibi F, Al-Ahdal MN, Murayama T, Dhalla M, Mukaida N, Taha M, Al-Sedairy S, Siddiqui Y, Kessie G, Matsushima K: The α chemokine, interleukin-8, inhibits the antiviral action of α. J Exp Med 1997, 186:1077-1085. interferon-α 73. Mizukoshi E, Kaneko S, Kaji K, Terasaki S, Matsushita E, Muraguchi M, Ohmoto Y, Kobayashi K: Serum levels of soluble interferon alpha/beta receptor as an inhibitory factor of interferon in the patients with chronic hepatitis C. Hepatology 1999, 30:1325-1331. β 74. Passwell JH, Shor R, Shoham J: The enhancing effect of interferon-β and -γγ on the killing of Leishmania tropica major in human mononuclear phagocytes in vitro. J Immunol 1986, 136:3062-3066. 75. Fujioka N, Akazawa R, Sakamoto K, Ohashi K, Kurimoto M: Potential application of human interferon-alpha in microbial infections of the oral cavity. J Interferon Cytokine Res 1995, 15:1047-1051. 76. Wilson CB, Westall J: Activation of neonatal and adult human macrophages by alpha, beta and gamma interferon. Infect Immun 1985, 49:351-356. 77.
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79. Orellana MA, Suzuki Y, Araujo F, Remington JS: Role of beta interferon in resistance to Toxoplasma gondii infection. Infect Immun 1991, 59:3287-3290. 80. Shankar AH, Morin P, Titus RG: Leishmania major: differential α/β β) and resistance to infection in C57BL/6 (high interferon-α α/β β) mice. Exp Parasitol congenic B6.C-H-28c (low interferon-α 1996, 84:136-143. 81. Denis M: Recombinant murine beta interferon enhances resistance of mice to systemic Mycobacterium avium infection. Infect Immun 1991, 59:1857-1859. 82. Nathan CF, Prendergast TJ, Wiebe ME, Stanley ER, Platzer E, Remold HG, Welte K, Rubin BY, Murray HW: Activation of human macrophages. Comparison of other cytokines with interferon-γγ. J Exp Med 1984, 160:600-605. 83. Murray HW, Szuro-Sudol A, Wellner D, Oca MJ, Granger AM, Libby DM, Rothermel CD, Rubin BY: Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferonstimulated human macrophages. Infect Immun 1989, 57:845-849. 84. Havell EA: Listeria monocytogenes-induced interferon-γγ primes the α/β β. host for production of tumor necrosis factor and interferon-α J Infect Dis 1993, 167:1364-1371. 85. Nakane A, Minagawa T: Induction of alpha and beta interferons during the hyporeactive state of gamma interferon by Mycobacterium bovis BCG cell wall fraction in Mycobacterium bovis BCG-sensitized mice. Infect Immun 1982, 36:966-970. 86. Diez B, Galdeano A, Nicolas R, Cisterna R: Relationship between the production of interferon-alpha/beta and interferon-gamma during acute toxoplasmosis. Parasitology 1989, 99:11-15. 87.
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88. Kierszenbaum F, Sonnenfeld G: Characterization of the antiviral activity produced during Trypanosoma cruzi infection and protective effects of exogenous interferon against experimental Chagas’ disease. J Parasitol 1982, 68:194-198. 89. Domanski P, Nadeau OW, Platanias LC, Fish E, Kellum M, Pitha P, Colamonici OR: Differential use of the βL subunit of the type I interferon (IFN) receptor determines signaling specificity for α2 and IFN-β β. J Biol Chem 1998, 273:3144-3147. IFN-α 90. Heim A, Stille-Seigener M, Pring-Akerblom P, Grumbach I, Brehm C, Kreuzer H, Figulla H-R: Recombinant interferons beta and gamma have a higher antiviral activity than interferon-alpha in coxsackievirus B3-infected carrier state cultures of human myocardial fibroblasts. J Interferon Cytokine Res 1995, 16:283-287. 91. Hoss-Homfeld A, Zwarthoff EC, Zawatzky R: Cell type specific expression and regulation of murine interferon alpha and beta genes. Virology 1989, 173:539-550. 92. Marie I, Durbin JE, Levy DE: Differential viral induction of distinct α genes by positive feedback through interferon interferon-α regulatory factor-7. EMBO J 1998, 17:6660-6669. 93. Iellem A, Colantonio L, Bhakta S, Sozzani S, Mantovani A, Sinigaglia F, α of I-309 and D'Ambrosio D: Inhibition by IL-12 and IFN-α macrophage-derived chemokine production upon TCR triggering of human Th1 cells. Eur J Immunol 2000, 30:1030-1039. 94. Hajnicka V, Kocakova P, Slovak M, Labuda M, Fuchsberger N, Nuttal PA: Inhibition of the antiviral action of interferon by tick salivary gland extract. Parasite Immunol 2000, 22:201-206.
The function of type I interferons in antimicrobial immunity Christian Bogdan Type I interferons (IFN-α and IFN-β) were originally described as potent antiviral substances, which are produced upon infection of animal cells with viruses. Despite a large body of literature that has accumulated during the past 25 years, their regulatory function in the immune system is still much less appreciated. Recent studies have highlighted the production of type I IFNs, their function in the immune response to infectious agents and the target cells of these interferons. Type I IFNs clearly affect the release of proinflammatory cytokines or nitric oxide by dendritic cells and macrophages, the capacity of type II interferon (IFN-γ) to activate phagocytes, the differentiation of T helper cells and the innate control of non-viral pathogens.
the interferon-regulatory factor 1 (IRF-1) were required whereas Jak2 was dispensable [7–13].
Current Opinion in Immunology 2000, 12:419–424
The potent activity of IFN-α/β against viral infections is based firstly on the expression of IFN-inducible protective genes (e.g. encoding 2′–5′oligoadenylate synthetase, doublestranded RNA-activated protein kinase, guanylate-binding protein and MxA protein) that confer cellular resistance, inhibit viral replication and impede viral dissemination and secondly on certain immunomodulatory effects [14–16]. Various other functions of IFN-α/β in the immune system — such as the modulation of antibody production, the enhancement of T cell and NK cell cytotoxicity, the inhibition of lymphocyte proliferation, the inhibition of suppressor T cells and the preferential differentiation of T helper cells into Th1 cells — have been recognized for quite some time and reviewed previously [17]. The present overview focuses on more recent data that are relevant to our understanding of the function of IFN-α/β in antimicrobial immunity.
0952-7915/00/$ — see front matter © 2000 Elsevier Science Ltd. All rights reserved.
α/β β and its regulation Production of IFN-α
Addresses Institute of Clinical Microbiology, Immunology and Hygiene, University of Erlangen, Wasserturmstrasse 3, D-91054 Erlangen, Germany; e-mail: [email protected]
Abbreviations LPS lipopolysaccharide MCMV mouse cytomegalovirus NOS2 type 2 nitric oxide synthase Stat1 signal transducer and activator of transcription 1
Introduction Type I interferons form an ancient family of cytokines that comprises IFN-α, IFN-β, IFN-δ, IFN-ω and IFN-τ. They are coded by intronless genes and are widely distributed amongst vertebrates. Whereas IFN-β is coded by a single gene in primates and rodents, more than 10 and 15 different subtypes of IFN-α have been found in mice and man, respectively. IFN-δ has been described in the pig, IFN-τ in cattle and sheep, and IFN-ω in cattle and humans [1]. Although all type I IFNs apparently exhibit antiviral and antiproliferative activities and thereby help to control viral infections and tumors [2–6], the role of type I IFNs in the immune system has been characterized in detail only for IFN-α and IFN-β (in the following text, these are collectively termed IFN-α/β). The action of IFN-α/β on target cells such as fibroblasts, T cells, macrophages or dendritic cells is mediated by the type I IFN receptor (a member of the class II helical cytokine receptor family) that consists of two subunits, the α-chain (IFNAR-1) and the β-chain (IFNAR-2). The latter has long (βL) and short (βS) forms. Mutational analyses and studies in gene-deficient mice revealed that for the induction of certain interferon response genes and/or for full (antiviral) activity of IFN-α or IFN-β, both receptor subunits, the Janus kinases Jak1 and Tyk2, signal transducer and activator of transcription 1 (Stat1) and, to some extent,
For a long time macrophages have been known to be a major cellular source of IFN-α/β in the immune system. Several studies have demonstrated a low-level constitutive expression of IFN-α/β already in resting macrophages ([17–19] and references therein). The production of IFNα/β by macrophages is upregulated upon infection with viruses, stimulation with double-stranded RNA or exposure to microbial pathogens (e.g. Chlamydia trachomatis, Escherichia coli, Listeria monocytogenes or Leishmania major) or to microbial products (e.g. lipopolysaccharide [LPS] or bacterial DNA) [20–23,24•]. Other sources of IFN-α/β include fibroblasts, NK cells, T cells, dendritic cells and a group of specialized leukocytes, the plasmacytoid monocytes ([17,25,26,27•,28••] and references therein). Recently, strong evidence was presented that the latter are precursors of dendritic cells. Plasmacytoid monocytes (which have a plasma-cell-like morphology) constitute a rare cell type that differs from monocytes and monocytederived dendritic cells by the absence of myeloid markers (e.g. CD11c, CD13 and CD33) and the production of high amounts of IFN-α/β in human peripheral blood upon infection with viruses or bacteria [26,27•,28••]. The various pro- and anti-inflammatory functions of IFNα/β (see below) necessitate a strict regulation of its production. Cytokines with known macrophage-inhibitory functions (e.g. IL-4 or IL-10) were also shown to suppress the production of IFN-α or IFN-β in mouse or human macrophages [18,29,30]. Apart from cytokines, the production of IFN-α/β is also regulated by inorganic molecules. In resting mouse peritoneal macrophages, constitutively released low levels of NO inhibited the expression of IFN-α4 mRNA and, to a minor extent, of IFN-β mRNA [31•].
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α/β β, IFN-γγ and macrophages IFN-α Macrophages function as host and effector cells for a large number of intracellular pathogens and are subject to the effects of numerous cytokines (including IFN-α/β) that are relevant in antimicrobial immunity. IFN-α/β markedly supports the differentiation of monocytes into dendritic cells with potent antigen-presenting activity, stimulates macrophage antibody-dependent cytotoxicity and positively or negatively regulates the production of various cytokines (e.g. TNF, IL-1, IL-6, IL-8, IL-12 and IL-18) by macrophages [21,32–34]. In addition, autocrine IFN-α/β is required for the enhancement of macrophage phagocytosis by M-CSF and IL-4 [35]. In human monocytes, recombinant IFN-α2b led to the induction of type 2 nitric oxide synthase (NOS2 or iNOS), an important antimicrobial effector pathway. In mouse macrophages, in contrast, exogenous IFN-α/β alone was unable to induce NOS2 but synergistic effects were observed in the presence of LPS or of L. major parasites (reviewed in [36]). Furthermore, autocrine IFN-α/β was essential for the induction of NOS2 by LPS or by viruses and IFN-γ [37,38]. On the other hand, pre-exposure of macrophages to IFN-α/β was shown to counteract several effects of IFN-γ, including the induction of MHC class II molecules, the downregulation of mannose-fucose receptor, the induction of cell death (apoptosis) and the expression of NOS2 ([36,39,40] and references therein). This unexpected heterogeneity of the effects of IFN-α/β on macrophages suggests that IFN-α/β can assume both protective and counter-protective functions during infectious diseases.
α/β β, IL-12, NK cells and T cells IFN-α IL-12, which is produced by macrophages and dendritic cells in response to cytokines and certain microbial stimuli, plays a pivotal role in the control of a large number of intracellular pathogens that is thought to result from its strong activating effects on NK cells and T cells. IFN-α/β has been shown to raise the levels of IL-12 and IL-18 mRNA in human macrophages and to synergize with IL-12 for the activation of NK cells to produce IFN-γ [17,21,41]. Similarly, IFN-α/β upregulated the expression of the IL-12 receptor β2 chain (IL-12Rβ2) in human CD4+ T cells and thereby facilitated their differentiation into IFN-γ-producing Th1 cells in response to IL-12 [42]. Although IFN-γ rather than IFN-α/β promoted the expression of IL-12Rβ2 and the subsequent IL-12-driven development of Th1 cells in naive mouse T cells [43,44], the overall experimental evidence clearly suggests that both IFN-α and IFN-β favor the generation of IFN-γ-producing CD4+ T cells in man and mice ([45–50]; see also Update). On the other hand, however, several studies demonstrated that IFN-α/β is a potent suppressor of the production of IL-12 as was seen in mixed splenic leukocyte populations or in cocultures of naive CD4+CD45RA+ T cells and dendritic cells as antigen-presenting cells [51,52•]. The negative regulatory effect of IFN-α/β was restricted to the induction of IL-12 that is mediated by CD40/CD40-ligand
and was not observed when dendritic cells were stimulated with LPS; IFN-α/β thus appears to interfere with a stimulatory signal elicited by CD40 [52•]. Taken together, these in vitro findings raise the question about the effect that endogenously produced (or therapeutically applied) IFN-α/β might have on the production of IL-12 and/or the development of Th1 cells in vivo. In mice infected with mouse cytomegalovirus (MCMV), neutralization of IFN-α/β or deletion of IFNAR-1 drastically increased the serum levels of IL-12 p40, IL-12 p70 and IFN-γ. Furthermore, during an ongoing MCMV infection, the ability of LPS to induce IL-12 was significantly suppressed but was restored upon treatment with anti-IFN-α/β. Thus, endogenous IFN-α/β can function as an inhibitor of IL-12 production in vivo, even if the IL-12 release is triggered by LPS [51]. It is possible that such a mechanism accounts for the T cell immunosuppression (and the increased susceptibility to intracellular bacteria or parasites) observed in patients with chronic viral infections (e.g. HIV) and a continuous upregulation of IFN-α/β [53]. On the other hand, recent clinical reports demonstrated that in patients who received a Mycobacterium bovis BCG immunotherapy for bladder cancer and in a patient who was suffering from chronic hepatitis C and progressive hepatic alveolar echinococcosis, treatment with recombinant human IFN-α2 led to enhanced Th1 cytokine responses (i.e. IFN-γ and IL-12) in vitro and in vivo [54,55]. These results are clearly preliminary and it is likely that both pro- and antiinflammatory effects occur during IFN-α/β treatment. Apart from governing the differentiation and cytokinesecretion pattern of T cells, IFN-α/β exerts a number of other effects on T cells; the significance of these effects during infectious diseases remains to be analysed. They include the rescue of activated or memory T cells from apoptosis [56•,57•], the induction of proliferation of memory-phenotype CD8+ T cells in the presence of antigen-presenting cells [58], the direct inhibition of proliferation of naive T cells [59,60] and the modulation of the chemokine receptor expression on the T cell surface (reviewed in [61]).
α/β β and infectious diseases IFN-α Viral infections
Studies with mice lacking IFNAR-I, IFN-β or Stat1α, or expressing tissue-specific type-I-IFN transgenes have demonstrated that type I IFNs control infections with a broad spectrum of viruses, including members of the family of poxviruses (vaccinia virus), herpesviridae (herpes simplex virus type 1 and MCMV), orthomyxoviruses (influenza A virus), paramyxoviridae (measles virus), arenaviruses (lymphocytic choriomeningitis virus [LCMV]), rhabdoviridae (vesicular stomatitis virus), picornaviridae (Theiler’s virus) and togaviridae (Semliki forest virus, Sindbis virus and Venezuelan equine encephalitis virus) [16,62–66,67•,68•]. In some of these infections, IFN-α/β was shown not only to directly suppress viral replication but also to specifically protect antigen-presenting cells (marginal zone macrophages
Type I interferons in antimicrobial immunity Bogdan
and dendritic cells) from productive infections with the virus and to prevent a fatal systemic inflammatory response syndrome (characterized by the release of IL-12, IFN-γ, TNF and IL-6) in the host organism [51,67•]. Furthermore, in the LCMV model, evidence was provided for the existence of two alternative pathways (IL-12- or IFN-α/β-dependent) each of which leads to a strong CD8+ T cell response and IFN-γ production and is sufficient to clear the infection in vivo [69••]. Another effector mechanism that is known to control the replication of certain viruses is the production of NO [36]. Although IFN-α/β is able to induce NO in the presence of a (viral) costimulus (see above), NOS2-deficient mice infected with hepatitis B virus were not resistant to the antiviral effects of endogenously produced IFN-α/β. This indicates that, at least in this model, the antiviral activity of IFN-α/β is NOS2-independent [70••]. In mice lacking a functional type I IFN receptor and in mice with an IFN-β gene deletion (but with unaltered IFN-α genes), the course of a vaccinia virus infection was aggravated to a similar degree compared with wild-type mice [7,68•]. This unexpected observation may be caused by the fact that, at least in vitro, the viral induction of IFN-α in fibroblasts (but not in leukocytes) was critically dependent on endogenous IFN-β [68•,71]. Future studies, however, will be necessary in order to clarify the regulatory relationship between the various type I IFNs in vivo. Host-cell-derived cytokines regulate not only the production but also the antiviral function of IFN-α/β. Notable examples of inhibitory factors for this function are firstly IL-8, a chemokine that is typically induced by a wide variety of viruses, and secondly the soluble IFN-α/β receptor ([72,73] and references therein; see also Update). Non-viral infections
Compared with viral infections, the role of type I IFNs for the defense against non-viral pathogens (i.e. bacteria, protozoa, fungi and helminths) has been considerably less well studied. Nevertheless, by now at least four interactions and functional relationships between these pathogens and IFN-α/β have been firmly established. First, treatment of macrophages (or neutrophils) with IFN-α or IFN-β enhanced their antimicrobial activity against C. psittaci, Mycobacterium avium, Toxoplasma gondii, Leishmania spp. or Candida albicans, particularly in the presence of endotoxin (LPS) [40,74–81]. However, it should be mentioned that induction of antimicrobial activity by IFN-α/β was not observed in other studies [82,83]. Second, in macrophages or fibroblasts certain bacteria or protozoa induce the production of IFN-α/β in vitro (see above). Third, IFN-α/β is produced during the immune response against bacterial or protozoan pathogens in vivo [23,84–86]. Fourth, recombinant mouse IFN-β protected mice against an infection with L. monocytogenes [87]; a similar protective effect of type I interferons was also seen in mice infected with Trypanosoma cruzi [88] or with T. gondii [79]. In mice infected with M. avium, the continuous application of IFN-β led
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to a one-log reduction of the bacterial burden in the liver and spleen [81]. In all four models, however, the function of endogenously produced IFN-α/β remains to be identified. In the mouse model of cutaneous leishmaniasis, IFN-α/β was already expressed at day one of infection with L. major in the skin lesion and was indispensable for the early expression of NOS2, the innate production of IFN-γ, the NK cell cytotoxic activity and the initial control of parasite spreading. Despite a severely impaired innate immune response, the neutralization of IFN-α/β four hours prior to and at the time of infection did not prevent the ultimate cure of the infection ([23]; C Bogdan, unpublished data). However, the course of L. major infection has not yet been evaluated under conditions of prolonged neutralization of endogenous IFN-α/β or in mice lacking type I IFN receptor signaling.
Functional differences between different type I IFNs? The existence of so many type I IFN genes raises the question about whether their protein products differ in their functions in the immune system. Although all type I IFNs are thought to signal through the same type I IFN receptor, there is evidence for differential receptor binding and signaling of IFN-α and IFN-β [13]. IFN-α2 and IFN-β were shown to require distinct intracytoplasmic regions of the βL chain to elicit an antiviral response and it was suggested that they differentially activate additional signaling molecules other than members of the Stat pathway ([89] and references therein). In vitro, recombinant IFN-β was much more active in clearing a persistent infection of human myocardial fibroblasts with coxsackievirus B3 than recombinant human IFN-α2 [90]. The virus-induced expression of the different IFN-α genes shows cell-type-dependent variations and appears to be differentially dependent on de novo protein synthesis and on Stat1 activation [91,92], which might be another source for heterogeneity. In vivo the antiviral efficacy of the IFN-α subtypes might indeed vary, as recently seen in MCMV-infected mice that were injected with plasmids expressing IFN-α1, IFN-α4 or IFN-α9. In this study, IFN-α1 turned out to exhibit the strongest antiviral effect but the possibility that the rate of production of each IFN subtype is not equivalent in situ could not be excluded [63].
Conclusions The potent antiviral function of IFN-α/β, which is due to both direct effects (i.e. mediating resistance to viruses) and indirect effects (i.e. immunostimulation), has been well established and has led to the approval of IFN-α for clinical use (e.g. treatment of chronic hepatitis B or C). Until now, the role of type I IFNs in defense against bacteria and parasites has been poorly studied but it is likely to be more complex than in viral infections. Based on the currently available data, protective and counter-protective effects of IFN-α/β can be envisaged because IFN-α/β exerts both agonistic and antagonistic effects on several components of the immune response that are critical for the control of intracellular bacteria or protozoa (e.g. synthesis of NO,
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synthesis of proinflammatory cytokines, macrophage activation by IFN-γ and the differentiation, activation or proliferation of T helper cells). Detailed in vivo analyses in animal models will be required before clinical application of IFN-α/β in non-viral infections can be considered.
Update α/β and T cells IFN-α
Recently, a novel mechanism by which IFN-α might promote and maintain an ongoing Th1 response was described [93]. IFN-α (as well as IL-12) inhibited the production of two chemokines (macrophage-derived chemokine [MDC] and I-309), which predominantly attract Th2 cells.
12. Kimura T, Nakayama K, Penninger J, Kitagawa M, Harada H, Matsuyama T, Tanaka N, Kamijo R, Vilcek J, Mak TW, Taniguchi T: Involvement of the IRF-1 transcription factor in antiviral responses to interferons. Science 1994, 264:1921-1924. 13. Mogensen KE, Lewerenz M, Reboul J, Lutfalla G, Uze G: The type I interferon receptor: structure, function and evolution of a family business. J Interferon Cytokine Res 1999, 19:1069-1098. 14. Sen GC, Ransohoff RM: Interferon-induced antiviral actions and their regulation. Adv Virus Res 1993, 42:57-102. 15. Hefti HP, Frese M, Landis H, Di Paolo C, Aguzzi A, Haller O, Pavlovic J: Human MxA protein protects mice lacking a functional alpha/beta interferon system against La crosse virus and other lethal viral infections. J Virol 1999, 73:6984-6991. 16. van den Broek MF, Müller U, Huang S, Zinkernagel RM, Aguet M: Immune defence in mice lacking type I and/or type II interferon receptors. Immunol Rev 1995, 148:5-18. 17.
α/β and viral infections IFN-α
Hajnicka et al. [94] have shown that the salivary gland extract of the tick, Dermacentor reticulans, inhibits the antiviral activity of purified mouse IFN-α/β. This finding might explain why ticks are efficient vectors of certain arboviruses.
Acknowledgements The author thanks Martin Röllinghoff and Ion Gresser for helpful comments on the manuscript. This research was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 263 A5).
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:
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