The interferons (IFN-s), also known as IL-28 and IL-29, are coexpressed with IFN-␤ after Toll-like-receptor (TLR) stimulation in human monocyte-derived dendritic cells (DCs). IFN-shares with type I IFNs an intracellular signaling pathway that drives the expression of a common set of genes. However, IFN-signaling is initiated through a membrane receptor system distinct from that of type I IFNs. Because IFNs produced by DCs in response to TLR stimulation are critical in the differentiation and maturation of DCs, we sought to investigate whether IFNexhibits specific effects on DC differentiation. In this work, we show that DCs acquire IFN-responsiveness through the expression of the specific IFN-receptor chain during their differentiation from monocytes. IFN--treated DCs express high levels of major histocompatibility complex class I (MHC class I) and MHC class II but low levels of costimulatory molecules. However, they express CCR7 and acquire the ability to migrate to lymph nodes when intravenously injected into SCID/Bg mice. In mixed lymphocyte reaction (MLR) cultures, IFN--treated DCs specifically induced IL-2-dependent proliferation of a CD4 ؉ CD25 ؉ Foxp3 ؉ T-cell subset with contact-dependent suppressive activity on T-cell proliferation initiated by fully mature DCs. IFN-s are thus able to generate tolerogenic DCs, an activity that could thwart IFN-␤ functions. IntroductionThe function of type I interferons (IFNs) in the regulation of the innate immune response is clearly established. [1][2][3] More recently, the importance of the type I IFN family (several ␣ subtypes and one ␤ subtype) in the generation of T cell-mediated adaptive immunity has emerged. 4,5 The fact that IFN-␤ is produced by dendritic cells (DCs) upon Toll-like-receptor (TLR) stimulation and can act as a differentiation and maturation factor on DCs has led to the concept that IFN-␤ is a cytokine linking innate and adaptive immunity. 6 However, type I IFNs are never produced alone: TLR-3 and TLR-4 stimulation of human monocyte-derived DCs, by their respective ligands, also induce the production of IFN-␤ and IFN-s. 7 The IFN-family was recently described. [8][9][10] It has 3 members: 1, 2, and 3, also known as IL-29, IL-28A, and IL-28B, respectively. IFN-s exhibit several common features with type I IFNs, including the ability to establish an antiviral state in sensitive cell lines, probably because IFN-s share with type I IFNs an intracellular signaling pathway that drives the expression of a common set of IFN-stimulated genes (ISGs). 11,12 However, IFNsignaling is initiated through a membrane receptor system distinct from that of type I IFN and composed of a unique IFN-LR1 subunit and the IL-10R2 chain, which is also part of the IL-10, IL-22, and IL-26 receptors. 13 The different receptor use of type I IFNs and IFN-s could give rise to unique signaling pathways in addition to recruitment of Stat1 and Stat2, both of which are activated by type I IFN and IFN-s through the Tyk2 and Jak1 kinases. Another important difference between type I IFN ...

Introduction: Human adenovirus (HAdV)-derived vectors have been used in numerous pre-clinical and clinical trials during the last 40 years. Current research in HAdV-based vaccines focuses on improving transgene immunogenicity and safety. Because pre-existing humoral immunity against HAdV types correlate with reduced vaccine efficacy and safety, many groups are exploring the development of HAdV types vectors with lower seroprevalence. However, global seroepidemiological data are incomplete. Areas covered: The goal of this review is to centralize 65 years of research on (primarily) HAdV epidemiology. After briefly addressing adenovirus biology, we chronical HAdV seroprevalence studies and highlight major milestones. Finally, we analyze data from about 50 studies with respect to HAdVs types that are currently used in the clinic, or are in the developmental pipeline. Expert opinion: Vaccination is among the most efficient tools to prevent infectious disease. HAdVbased vaccines have undeniable potential, but optimization is needed and antivector immunity remains a challenge if the same vectors are to be administrated to different populations. Here, we identify gaps in our knowledge and the need for updated worldwide epidemiological data.

Acute and lethal ileitis can be elicited in certain strains of inbred mice after oral infection with the intracellular protozoan parasite Toxoplasma gondii. The development of this inflammatory process is dependent upon the induction of a robust Th1 response, including overproduction of IFN-γ, TNF-α, and NO, as has been reported in other experimental models of human inflammatory bowel disease. In this study we have investigated the role of CD4+ T cells from the lamina propria (LP) in the early inflammatory events after T. gondii infection using isolated and primary cultured intestinal cells from infected mice and immortalized mouse mICcl2 intestinal epithelial cells. Primed LP CD4+ T cells isolated from parasite-infected mice produce substantial quantities of both IFN-γ and TNF-α. IFN-γ- and TNF-α-producing LP CD4+ T cells synergize with infected mICcl2 and enhance the production of several inflammatory chemokines including macrophage-inflammatory protein-2, monocyte chemoattractant protein-1, monocyte chemoattractant protein-3, macrophage-inflammatory protein-1αβ, and IFN-γ-inducible protein-10. Furthermore, primed LP CD4+ T cells cocultured with infected mICcl2 inhibited replication of the parasite in the intestinal epithelial cells. Thus, LP CD4+ T cells can interact with parasite-infected intestinal epithelial cells and alter the expression of several proinflammatory products that have been associated with the development of intestinal inflammation. The interaction between these two components of the gut mucosal compartment (CD4+ T cells and enterocytes) may play a role in the immunopathogenesis of this pathogen-driven experimental inflammatory bowel disease model.

Human adenoviruses (HAdVs) are nonenveloped proteinaceous particles containing a linear double-stranded DNA genome. HAdVs cause a spectrum of pathologies in all populations regardless of health standards. Following repeat exposure to multiple HAdV types, we develop robust and long-lived humoral and cellular immune responses that provide life-long protection from de novo infections and persistent HAdV. How HAdVs, anti-HAdV antibodies and antigen presenting cells (APCs) interact to influence infection is still incompletely understood. In our study, we used physical, pharmacological, biochemical, fluorescence and electron microscopy, molecular and cell biology approaches to dissect the impact of immune-complexed HAdV (IC-HAdV) on human monocyte-derived dendritic cells (MoDCs). We show that IC-HAdV generate stabilized complexes of ~200 nm that are efficiently internalized by, and aggregate in, MoDCs. By comparing IC-HAdV, IC-empty capsid, IC-Ad2ts1 (a HAdV-C2 impaired in endosomal escape due to a mutation that impacts protease encapsidation) and IC-AdL40Q (a HAdV-C5 impaired in endosomal escape due to a mutation in protein VI), we demonstrate that protein VI-dependent endosomal escape is required for the HAdV genome to engage the DNA pattern recognition receptor AIM2 (absent in melanoma 2). AIM2 engagement induces pyroptotic MoDC death via ASC (apoptosis-associated speck protein containing a caspase activation/recruitment domain) aggregation, inflammasome formation, caspase 1 activation, and IL-1β and gasdermin D (GSDMD) cleavage. Our study provides mechanistic insight into how humoral immunity initiates an innate immune response to HAdV-C5 in human professional APCs.

Although it has been known for 50 years that adenoviruses (Ads) interact with erythrocytes ex vivo, the molecular and structural basis for this interaction, which has been serendipitously exploited for diagnostic tests, is unknown. In this study, we characterized the interaction between erythrocytes and unrelated Ad serotypes, human 5 (HAd5) and 37 (HAd37), and canine 2 (CAV-2). While these serotypes agglutinate human erythrocytes, they use different receptors, have different tropisms and/or infect different species. Using molecular, biochemical, structural and transgenic animal-based analyses, we found that the primary erythrocyte interaction domain for HAd37 is its sialic acid binding site, while CAV-2 binding depends on at least three factors: electrostatic interactions, sialic acid binding and, unexpectedly, binding to the coxsackievirus and adenovirus receptor (CAR) on human erythrocytes. We show that the presence of CAR on erythrocytes leads to prolonged in vivo blood half-life and significantly reduced liver infection when a CAR-tropic Ad is injected intravenously. This study provides i) a molecular and structural rationale for Ad–erythrocyte interactions, ii) a basis to improve vector-mediated gene transfer and iii) a mechanism that may explain the biodistribution and pathogenic inconsistencies found between human and animal models.

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In humans, type I interferon (IFN) is a family of 17 cytokines, among which the ␣ subtypes and the ␤ subtype are differentially expressed. It has been suggested that IFN-␤ activates a specific signaling cascade in addition to those activated by all type I IFNs. Nevertheless, no true biological relevance for a differential activity of ␣ and ␤ IFN subtypes has been identified so far. Because type I IFNs are critical for the regulation of osteoclastogenesis in mice, we have compared the effect of IFN-␣2 and IFN-␤ on the differentiation of human monocytes into osteoclasts. Primary monocytes undergoing osteoclastic differentiation are highly and equally sensitive to both ␣2 and ␤ IFNs as determined by measuring the induction levels of several IFN-stimulated genes. However, IFN-␤ was 100-fold more potent than the ␣2 subtype at inhibiting osteoclastogenesis. Expression profiling of the genes differentially regulated by IFN-␣2 and IFN-␤ in this cellular system revealed the chemokine CXCL11 as the only IFN-induced gene differentially up-regulated by IFN-␤. We show that recombinant CXCL11 by itself inhibits osteoclastic differentiation. These results indicate that autocrine-acting CXCL11 mediates, at least in part, the regulations of osteoclastogenesis by type I IFNs.cytokine ͉ osteoclast

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