Showing papers on "Interferon published in 2005"

IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction

Abstract: Type I interferons are central mediators for antiviral responses. Using high-throughput functional screening of interferon inducers, we have identified here a molecule we call interferon-beta promoter stimulator 1 (IPS-1). Overexpression of IPS-1 induced type I interferon and interferon-inducible genes through activation of IRF3, IRF7 and NF-kappaB transcription factors. TBK1 and IKKi protein kinases were required for the IPS-1-mediated interferon induction. IPS-1 contained an N-terminal CARD-like structure that mediated interaction with the CARD of RIG-I and Mda5, which are cytoplasmic RNA helicases that sense viral infection. 'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection. Thus, IPS-1 is an adaptor involved in RIG-I- and Mda5-mediated antiviral immune responses.

IRF-7 is the master regulator of type-I interferon-dependent immune responses

Abstract: The type-I interferon (IFN-alpha/beta) response is critical to immunity against viruses and can be triggered in many cell types by cytosolic detection of viral infection, or in differentiated plasmacytoid dendritic cells by the Toll-like receptor 9 (TLR9) subfamily, which generates signals via the adaptor MyD88 to elicit robust IFN induction. Using mice deficient in the Irf7 gene (Irf7-/- mice), we show that the transcription factor IRF-7 is essential for the induction of IFN-alpha/beta genes via the virus-activated, MyD88-independent pathway and the TLR-activated, MyD88-dependent pathway. Viral induction of MyD88-independent IFN-alpha/beta genes is severely impaired in Irf7-/- fibroblasts. Consistently, Irf7-/- mice are more vulnerable than Myd88-/- mice to viral infection, and this correlates with a marked decrease in serum IFN levels, indicating the importance of the IRF-7-dependent induction of systemic IFN responses for innate antiviral immunity. Furthermore, robust induction of IFN production by activation of the TLR9 subfamily in plasmacytoid dendritic cells is entirely dependent on IRF-7, and this MyD88-IRF-7 pathway governs the induction of CD8+ T-cell responses. Thus, all elements of IFN responses, whether the systemic production of IFN in innate immunity or the local action of IFN from plasmacytoid dendritic cells in adaptive immunity, are under the control of IRF-7.

Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7.

Abstract: Short interfering RNA (siRNA) is used in RNA interference technology to avoid non-target-related induction of type I interferon (IFN) typical for long double-stranded RNA. Here we show that in plasmacytoid dendritic cells (PDC), an immune cell subset specialized in the detection of viral nucleic acids and production of type I IFN, some siRNA sequences, independent of their GU content, are potent stimuli of IFN-alpha production. Localization of the immunostimulatory motif on the sense strand of a potent IFN-alpha-inducing siRNA allowed dissection of immunostimulation and target silencing. Injection into mice of immunostimulatory siRNA, when complexed with cationic liposomes, induced systemic immune responses in the same range as the TLR9 ligand CpG, including IFN-alpha in serum and activation of T cells and dendritic cells in spleen. Immunostimulation by siRNA was absent in TLR7-deficient mice. Thus sequence-specific TLR7-dependent immune recognition in PDC needs to be considered as an additional biological activity of siRNA, which then should be termed immunostimulatory RNA (isRNA).

Plasmacytoid predendritic cells initiate psoriasis through interferon-α production

Abstract: Psoriasis is one of the most common T cell-mediated autoimmune diseases in humans. Although a role for the innate immune system in driving the autoimmune T cell cascade has been proposed, its nature remains elusive. We show that plasmacytoid predendritic cells (PDCs), the natural interferon (IFN)-alpha-producing cells, infiltrate the skin of psoriatic patients and become activated to produce IFN-alpha early during disease formation. In a xenograft model of human psoriasis, we demonstrate that blocking IFN-alpha signaling or inhibiting the ability of PDCs to produce IFN-alpha prevented the T cell-dependent development of psoriasis. Furthermore, IFN-alpha reconstitution experiments demonstrated that PDC-derived IFN-alpha is essential to drive the development of psoriasis in vivo. These findings uncover a novel innate immune pathway for triggering a common human autoimmune disease and suggest that PDCs and PDC-derived IFN-alpha represent potential early targets for the treatment of psoriasis.

Mechanism of action of interferon and ribavirin in treatment of hepatitis C

Abstract: Since the identification of the hepatitis C virus, great strides have been made in the development of an antiviral therapy. As a crucial mediator of the innate antiviral immune response, interferon-alpha (IFN-alpha) was a natural choice for treatment. Whereas treatment with IFN-alpha alone achieved only modest success, the addition of the broad-spectrum antiviral agent ribavirin greatly improved responses. However, half of the infected individuals with chronic disease do not achieve sustained clearance of hepatitis C virus. To optimize current therapeutic strategies and to develop new therapies, a better understanding of the mechanism of action of IFN and ribavirin will be essential.

Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus

Abstract: Raised serum levels of interferon (IFN)- � have been observed in systemic lupus erythematosus (SLE) patients, and these levels are correlated with both disease activity and severity. The origin of this IFN- � is still unclear, but increasing evidence suggests the critical involvement of activated plasmacytoid predendritic cells (PDCs). In SLE patients, DNA and RNA viruses, as well as immune complexes (ICs), that consist of autoantibodies specific to self-DNA and RNA protein particles can stimulate production of IFN- � . We have developed three series of oligonucleotide (ODN)-based inhibitors of Toll-like receptor (TLR) signaling. These ODNs include inhibitors of TLR9, inhibitors of TLR7 but not TLR9, and sequences that inhibit both TLR7 and TLR9. Specificity of these inhibitors is confirmed by inhibition of IFN- � production by PDCs in response to DNA or RNA viruses. We show that mammalian DNA and RNA, in the form of ICs, are potent self-antigens for TLR9 and TLR7, respectively, and induce IFN- � production by PDCs. This work suggests that TLRs may have a critical role in the promotion of lupus through the induction of IFN- � by PDCs. These inhibitors of TLR signaling thus represent novel therapeutic agents with potential for the treatment of lupus.

Regulating Intracellular Antiviral Defense and Permissiveness to Hepatitis C Virus RNA Replication through a Cellular RNA Helicase, RIG-I

Abstract: Virus-responsive signaling pathways that induce alpha/beta interferon production and engage intracellular immune defenses influence the outcome of many viral infections. The processes that trigger these defenses and their effect upon host permissiveness for specific viral pathogens are not well understood. We show that structured hepatitis C virus (HCV) genomic RNA activates interferon regulatory factor 3 (IRF3), thereby inducing interferon in cultured cells. This response is absent in cells selected for permissiveness for HCV RNA replication. Studies including genetic complementation revealed that permissiveness is due to mutational inactivation of RIG-I, an interferon-inducible cellular DExD/H box RNA helicase. Its helicase domain binds HCV RNA and transduces the activation signal for IRF3 by its caspase recruiting domain homolog. RIG-I is thus a pathogen receptor that regulates cellular permissiveness to HCV replication and, as an interferon-responsive gene, may play a key role in interferon-based therapies for the treatment of HCV infection.

Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction.

Abstract: Robust type-I interferon (IFN-alpha/beta) induction in plasmacytoid dendritic cells, through the activation of Toll-like receptor 9 (TLR9), constitutes a critical aspect of immunity. It is absolutely dependent on the transcription factor IRF-7, which interacts with and is activated by the adaptor MyD88. How plasmacytoid dendritic cells, but not other cell types (such as conventional dendritic cells), are able to activate the MyD88-IRF-7-dependent IFN induction pathway remains unknown. Here we show that the spatiotemporal regulation of MyD88-IRF-7 signalling is critical for a high-level IFN induction in response to TLR9 activation. The IFN-inducing TLR9 ligand, A/D-type CpG oligodeoxynucleotide (CpG-A), is retained for long periods in the endosomal vesicles of plasmacytoid dendritic cells, together with the MyD88-IRF-7 complex. However, in conventional dendritic cells, CpG-A is rapidly transferred to lysosomal vesicles. We further show that conventional dendritic cells can also mount a robust IFN induction if CpG-A is manipulated for endosomal retention using a cationic lipid. This strategy also allows us to demonstrate endosomal activation of the IFN pathway by the otherwise inactive TLR9 ligand B/K-type oligodeoxynucleotide (CpG-B). Thus, our study offers insights into the regulation of TLR9 signalling in space, potentially suggesting a new avenue for therapeutic intervention.

Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling.

Abstract: Hepatitis C virus (HCV) is a major human pathogen that infects 170 million people. A hallmark of HCV is its ability to establish persistent infections reflecting the evasion of host immunity and interference with α/β-IFN innate immune defenses. We demonstrate that disruption of retinoic acid-inducible gene I (RIG-I) signaling by the viral NS3/4A protease contributes to the ability of HCV to control innate antiviral defenses. RIG-I was essential for virus or HCV RNA-induced signaling to the IFN-β promoter in human hepatoma cells. This signaling was disrupted by the protease activity of NS3/4A, which ablates RIG-I signaling of downstream IFN regulatory factor 3 and NF-κB activation, attenuating expression of host antiviral defense genes and interrupting an IFN amplification loop that otherwise suppresses HCV replication. Treatment of cells with an active site inhibitor of the NS3/4A protease relieved this suppression and restored intracellular antiviral defenses. Thus, NS3/4A control of RIG-I supports HCV persistence by preventing IFN regulatory factor 3 and NF-κB activation. Our results demonstrate that these processes are amenable to restoration through pharmacologic inhibition of viral protease function.

A critical function for type I interferons in cancer immunoediting

Abstract: 'Cancer immunoediting' is a process wherein the immune system protects hosts against tumor development and facilitates outgrowth of tumors with reduced immunogenicity. Although interferon-γ (IFN-γ) is known to be involved in this process, the involvement of type I interferons (IFN-α/β) has not been elucidated. We now show that, like IFN-γ, endogenously produced IFN-α/β was required for the prevention of the growth of primary carcinogen–induced and transplantable tumors. Although tumor cells are important IFN-γ targets, they are not functionally relevant sites of the actions of the type I interferons. Instead, host hematopoietic cells are critical IFN-α/β targets during development of protective antitumor responses. Therefore, type I interferons are important components of the cancer immunoediting process and function in a way that does not completely overlap the functions of IFN-γ.

A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells.

Abstract: Dendritic cells (DC) produce interleukin-12 (IL-12) in response to Toll-like receptor (TLR) activation. Two major TLR signaling pathways participate in the response to pathogens: the nuclear factor-κB (NF-κB)–dependent pathway leading to inflammatory cytokine secretion including IL-12 and the interferon (IFN)-dependent pathway inducing type I IFN and IFN-regulated genes. Here we show that the two pathways cooperate and are likely both necessary for inducing an optimal response to pathogens. R-848/Resiquimod (TLR7 ligand in the mouse and TLR7/8 ligand in human) synergized with poly(I:C) (TLR3 ligand) or lipopolysaccharide (LPS; TLR4 ligand) in inducing high levels of bioactive IL-12p70 secretion and IFN-β mRNA accumulation by mouse bone marrow–derived DC (BM-DC). Strikingly, IL-12p70 but not IL-12p40 secretion was strongly reduced in BM-DC from STAT1−/− and IFNAR−/− mice. STAT1 tyrosine-phosphorylation, IL-12p35, and IFN-β mRNA accumulation were strongly inhibited in IFNAR−/− BM-DC activated with the TLR ligand combinations. Similar observation were obtained in human TLR8-expressing monocyte-derived DC (moDC) using neutralizing anti-IFNAR2 antibodies, although results also pointed to a possible involvement of IFN-λ1 (also known as IL-29). This suggests that TLR engagement on DC induces endogenous IFNs that further synergize with the NF-κB pathway for optimal IL-12p70 secretion. Moreover, analysis of interferon regulatory factors (IRF) regulation in moDC suggests a role for IRF7/8 in mediating IRF3-independent type I IFN and possibly IL-12p35 synthesis in response to TLR7/8.

Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8

Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies to certain cellular macromolecules, such as the small nuclear ribonucleoprotein particles (snRNPs), which had been considered to be passive targets of the autoimmune response. SLE is also characterized by the increased expression of type I interferon (IFN), which appears to be associated with the development and severity of disease. Here, we show that specific, highly conserved RNA sequences within snRNPs can stimulate Toll-like receptors (TLRs) 7 and 8 as well as activate innate immune cells, such as plasmacytoid dendritic cells (pDCs), which respond by secreting high levels of type I IFN. SLE patient sera containing autoantibodies to snRNPs form immune complexes that are taken up through the Fc receptor gammaRII and efficiently stimulate pDCs to secrete type I IFNs. These results demonstrate that a prototype autoantigen, the snRNP, can directly stimulate innate immunity and suggest that autoantibodies against snRNP may initiate SLE by stimulating TLR7/8.

Inhibition of Alpha/Beta Interferon Signaling by the NS4B Protein of Flaviviruses

Abstract: Flaviviruses are insect-borne, positive-strand RNA viruses that have been disseminated worldwide. Their genome is translated into a polyprotein, which is subsequently cleaved by a combination of viral and host proteases to produce three structural proteins and seven nonstructural proteins. The nonstructural protein NS4B of dengue 2 virus partially blocks activation of STAT1 and interferon-stimulated response element (ISRE) promoters in cells stimulated with interferon (IFN). We have found that this function of NS4B is conserved in West Nile and yellow fever viruses. Deletion analysis shows that that the first 125 amino acids of dengue virus NS4B are sufficient for inhibition of alpha/beta IFN (IFN-α/β) signaling. The cleavable signal peptide at the N terminus of NS4B, a peptide with a molecular weight of 2,000, is required for IFN antagonism but can be replaced by an unrelated signal peptide. Coexpression of dengue virus NS4A and NS4B together results in enhanced inhibition of ISRE promoter activation in response to IFN-α/β. In contrast, expression of the precursor NS4A/B fusion protein does not cause an inhibition of IFN signaling unless this product is cleaved by the viral peptidase NS2B/NS3, indicating that proper viral polyprotein processing is required for anti-interferon function.

The Yin and Yang of type I interferon activity in bacterial infection

Abstract: Interferons (IFNs) are cytokines that are important for immune responses, particularly to intracellular pathogens. They are divided into two structurally and functionally distinct types that interact with different cell-surface receptors. Classically, type I IFNs are potent antiviral immunoregulators, whereas the type II IFN enhances antibacterial immunity. However, as outlined here, type I IFNs are also produced in response to infection with other pathogens, and an increasing body of work shows that type I IFNs have an important role in the host response to bacterial infection. Strikingly, their activity can be either favourable or detrimental, and can influence various immune effector mechanisms.

Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction

Abstract: Toll-like receptors (TLRs) recognize microbial pathogens and trigger innate immune responses. Among TLR family members, TLR7, TLR8, and TLR9 induce interferon (IFN)-alpha in plasmacytoid dendritic cells (pDCs). This induction requires the formation of a complex consisting of the adaptor MyD88, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and IFN regulatory factor (IRF) 7. Here we show an essential role of IL-1 receptor-associated kinase (IRAK)-1 in TLR7- and TLR9-mediated IRF7 signaling pathway. IRAK-1 directly bound and phosphorylated IRF7 in vitro. The kinase activity of IRAK-1 was necessary for transcriptional activation of IRF7. TLR7- and TLR9-mediated IFN-alpha production was abolished in Irak-1-deficient mice, whereas inflammatory cytokine production was not impaired. Despite normal activation of NF-kappaB and mitogen-activated protein kinases, IRF7 was not activated by a TLR9 ligand in Irak-1-deficient pDCs. These results indicated that IRAK-1 is a specific regulator for TLR7- and TLR9-mediated IFN-alpha induction in pDCs.

Lambda Interferon Inhibits Hepatitis B and C Virus Replication

Abstract: Lambda interferon (IFN-λ) induces an intracellular IFN-α/β-like antiviral response through a receptor complex distinct from the IFN-α/β receptor. We therefore determined the ability of IFN-λ to inhibit hepatitis B virus (HBV) and hepatitis C virus (HCV) replication. IFN-λ inhibits HBV replication in a differentiated murine hepatocyte cell line with kinetics and efficiency similar to IFN-α/β and does not require the expression of IFN-α/β or IFN-γ. Furthermore, IFN-λ blocked the replication of a subgenomic and a full-length genomic HCV replicon in human hepatocyte Huh7 cells. These results suggest the possibility that IFN-λ may be therapeutically useful in the treatment of chronic HBV or HCV infection.

NETWORK COMMUNICATIONS: Lymphotoxins, LIGHT, and TNF

Abstract: Lymphotoxins (LT) provide essential communication links between lymphocytes and the surrounding stromal and parenchymal cells and together with the two related cytokines, tumor necrosis factor (TNF) and LIGHT (LT-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells), form an integrated signaling network necessary for efficient innate and adaptive immune responses. Recent studies have identified signaling pathways that regulate several genes, including chemokines and interferons, which participate in the development and function of microenvironments in lymphoid tissue and host defense. Disruption of the LT/TNF/LIGHT network alleviates inflammation in certain autoimmune disease models, but decreases resistance to selected pathogens. Pharmacological disruption of this network in human autoimmune diseases such as rheumatoid arthritis alleviates inflammation in a significant number of patients, but not in other diseases, a finding that challenges our molecular paradigms of autoimmunity and perhaps will reveal novel roles for this network in pathogenesis.

Accelerated CD8 + T-cell memory and prime-boost response after dendritic-cell vaccination

Abstract: Efficient boosting of memory T-cell numbers to protective levels generally requires a relatively long interval between immunizations. Decreasing this interval could be crucial in biodefense and cancer immunotherapy, in which rapid protective responses are essential. Here, we show that vaccination with peptide-coated dendritic cells (DCs) generated CD8+ T cells with the phenotype and function of memory cells within 4-6 d. These early memory CD8+ T cells underwent vigorous secondary expansion in response to a variety of booster immunizations, leading to elevated numbers of effector and memory T cells and enhanced protective immunity. Coinjection of CpG oligodeoxynucleotides, potent inducers of inflammation that did not alter the duration of DC antigen display, prevented the rapid generation of memory T cells in wild-type mice but not in mice lacking the interferon (IFN)-gamma receptor. These data show that DC vaccination stimulates a pathway of accelerated generation of memory T cells, and suggest that events of inflammation, including the action of IFN-gamma on the responding T cells, control the rate of development of memory CD8+ T cells.

Cytokine Responses in Severe Acute Respiratory Syndrome Coronavirus-Infected Macrophages In Vitro: Possible Relevance to Pathogenesis

Abstract: The pathogenesis of severe acute respiratory syndrome (SARS) remains unclear. Macrophages are key sentinel cells in the respiratory system, and it is therefore relevant to compare the responses of human macrophages to infections with the SARS coronavirus (SARS-CoV) and other respiratory viruses. Primary human monocyte-derived macrophages were infected with SARS-CoV in vitro. Virus replication was monitored by measuring the levels of positive- and negative-strand RNA, by immunofluorescence detection of the SARS-CoV nucleoprotein, and by titration of the infectious virus. The gene expression profiles of macrophages infected with SARS-CoV, human coronavirus 229E, and influenza A (H1N1) virus were compared by using microarrays and real-time quantitative reverse transcriptase PCR. Secreted cytokines were measured with an enzyme-linked immunosorbent assay. SARS-CoV initiated viral gene transcription and protein synthesis in macrophages, but replication was abortive and no infectious virus was produced. In contrast to the case with human coronavirus 229E and influenza A virus, there was little or no induction of beta interferon (IFN-β) in SARS-CoV-infected macrophages. Furthermore, SARS-CoV induced the expression of chemokines such as CXCL10/IFN-γ-inducible protein 10 and CCL2/monocyte chemotactic protein 1. The poor induction of IFN-β, a key component of innate immunity, and the ability of the virus to induce chemokines could explain aspects of the pathogenesis of SARS.

Activation of the type I interferon system in primary Sjogren's syndrome : a possible etiopathogenic mechanism

Abstract: Objective The etiopathogenesis of primary Sjogren's syndrome (SS) is largely unknown. In other autoimmune diseases, type I interferon (IFN) may play a pivotal role by triggering and sustaining the disease process. We therefore aimed to determine whether patients with primary SS had an activated type I IFN system. Methods Salivary gland biopsy specimens and sera from patients with primary SS were investigated for the occurrence of IFNα-producing cells and measurable IFNα levels, respectively. The ability of primary SS sera together with apoptotic or necrotic cells to induce IFNα production in normal peripheral blood mononuclear cells was examined. The IFNα inducer was characterized, and IFNα-producing cells were identified. Clinical data were correlated with the IFNα-inducing capacity of primary SS sera. Results Numerous IFNα-producing cells were detected in salivary gland biopsy specimens, despite low serum IFNα levels. Autoantibodies to RNA-binding proteins, combined with material released by necrotic or late apoptotic cells, were potent inducers of IFNα production in plasmacytoid dendritic cells (PDCs). This appeared to be attributable to RNA-containing immune complexes triggering PDCs by means of RNA and interaction with Fcγ receptor IIa. The IFNα-inducing capacity of sera was associated with positive results of a labial salivary gland biopsy (focus score ≥1) and with dermatologic, hematologic, and pulmonary manifestations. Conclusion Patients with primary SS have an activated type I IFN system. Although virus may initiate the production of IFN, the continued IFNα synthesis is caused by RNA-containing immune complexes that activate PDCs to prolong IFNα production at the tissue level. This IFNα promotes the autoimmune process by a vicious circle–like mechanism, with increased autoantibody production and formation of more endogenous IFNα inducers.

Vaccinia virus protein A46R targets multiple Toll-like–interleukin-1 receptor adaptors and contributes to virulence

Abstract: Viral immune evasion strategies target key aspects of the host antiviral response. Recently, it has been recognized that Toll-like receptors (TLRs) have a role in innate defense against viruses. Here, we define the function of the vaccinia virus (VV) protein A46R and show it inhibits intracellular signalling by a range of TLRs. TLR signalling is triggered by homotypic interactions between the Toll-like–interleukin-1 resistance (TIR) domains of the receptors and adaptor molecules. A46R contains a TIR domain and is the only viral TIR domain–containing protein identified to date. We demonstrate that A46R targets the host TIR adaptors myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like, TIR domain–containing adaptor inducing IFN-β (TRIF), and the TRIF-related adaptor molecule and thereby interferes with downstream activation of mitogen-activated protein kinases and nuclear factor κB. TRIF mediates activation of interferon (IFN) regulatory factor 3 (IRF3) and induction of IFN-β by TLR3 and TLR4 and suppresses VV replication in macrophages. Here, A46R disrupted TRIF-induced IRF3 activation and induction of the TRIF-dependent gene regulated on activation, normal T cell expressed and secreted. Furthermore, we show that A46R is functionally distinct from another described VV TLR inhibitor, A52R. Importantly, VV lacking the A46R gene was attenuated in a murine intranasal model, demonstrating the importance of A46R for VV virulence.

The host type I interferon response to viral and bacterial infections.

Abstract: Type I interferons (IFN) are well studied cytokines with anti-viral and immune-modulating functions. Type I IFNs are produced following viral infections, but until recently, the mechanisms of viral recognition leading to IFN production were largely unknown. Toll like receptors (TLRs) have emerged as key transducers of type I IFN during viral infections by recognizing various viral components. Furthermore, much progress has been made in defining the signaling pathways downstream of TLRs for type I IFN production. TLR7 and TLR9 have become apparent as universally important in inducing type I IFN during infection with most viruses, particularly by plasmacytoid dendritic cells. New intracellular viral pattern recognition receptors leading to type I IFN production have been identified. Many bacteria can also induce the up-regulation of these cytokines. Interestingly, recent studies have found a detrimental effect on host cells if type I IFN is produced during infection with the intracellular gram-positive bacterial pathogen, Listeria monocytogenes. This review will discuss the recent advances made in defining the signaling pathways leading to type I IFN production.

Protection from cytomegalovirus after transplantation is correlated with immediate early 1–specific CD8 T cells

Abstract: T cells are crucial for the control of cytomegalovirus (CMV) in infected individuals. Although CMV-specific T cells can be quantified by various methods, clear correlates of protection from CMV disease have not been defined. However, responses to the pp65 protein are believed to play an important role. Here, the proportions of interferon γ–producing T cells following ex vivo activation with pools of overlapping peptides representing the pp65 and immediate early (IE)-1 proteins were determined at multiple time points and related to the development of CMV disease in 27 heart and lung transplant recipients. Frequencies of IE-1–specific CD8 T cells above 0.2 and 0.4% at day 0 and 2 wk, respectively, or 0.4% at any time during the first months discriminated patients who did not develop CMV disease from patients at risk, 50–60% of whom developed CMV disease. No similar distinction between risk groups was possible based on pp65-specific CD8 or CD4 T cell responses. Remarkably, CMV disease developed exclusively in patients with a dominant pp65-specific CD8 T cell response. In conclusion, high frequencies of IE-1 but not pp65-specific CD8 T cells correlate with protection from CMV disease. These results have important implications for monitoring T cell responses, adoptive cell therapy, and vaccine design.

Regulation of the type I IFN induction: a current view

Abstract: The type I IFN-alpha/beta gene family was identified about a quarter of a century ago as a prototype of many cytokine gene families, which led to the subsequent burst of studies on molecular mechanisms underlying cytokine gene expression and signaling. Although originally discovered for their activity to confer an antiviral state on cells, more evidence has recently been emerging regarding IFN-alpha/beta actions on cell growth, differentiation and many immunoregulatory activities, which are of even greater fundamental biological significance. Indeed, much attention has recently been focused on the induction and function of the IFN-alpha/beta system regulated by Toll-like receptors (TLRs), which are critical for linking the innate and adaptive immunities. The understanding of the regulatory mechanisms of IFN-alpha/beta gene induction by TLRs and viruses is an emerging theme, for which much new insight has been gained over the past few years.