No abstract

Type I IFN are cytokines which play a central role in host resistance to viral or microbial infections and are important components linking innate and adaptive immunity. We and others have previously demonstrated that the production of IFN-b by DC following bacterial infections or TLR triggering influences, in an autocrine manner, their maturation. In this study, we investigated whether IFN-b release modulates the phenotype of the immature DC and their response to a subsequent TLR stimulation. The induction of CD86, HLA-DR, CD38 and B7H1 and the absence of CCR7 and CD83 expression upon IFN-b treatment suggest that IFN-b-primed DC remain at the site of infection acquiring an activated phenotype. These results prompted us to investigate the response of IFN-b-primed DC to TLR stimulation. While IFN-b pretreatment increases slightly the expression of maturation markers in TLR2-or TLR4-stimulated DC, it is able to modulate selectively the secretion of inflammatory and immuno-regulating cytokines. Interestingly, IL-27p28 subunit was induced by IFN-b alone or during LPS-induced maturation of DC in a type I IFN-dependent manner through IFN regulatory factor-1 (IRF-1) activation. Taken together, our results shed light on the capacity of IFN-b to finely tune DC response to invading pathogens.

Aspergillus fumigatus is the most prevalent airborne fungal pathogen and causes fatal invasive aspergillosis in immunocompromised patients. Given the essential role of dendritic cells (DC) in initiating and regulating immune responses, we investigated the impact of A. fumigatus conidial infection on human DC. A. fumigatus conidia were rapidly internalized and induced the release of tumor necrosis factor alpha within the first 8 h. After A. fumigatus infection, the majority of DC underwent full maturation, although CCR7 expression was observed only in DC that had internalized the conidia. Additionally, the analysis of regulatory cytokines showed that infected DC simultaneously produced interleukin-12p70 (IL-12p70) and significant amounts of IL-10. IL-10 neutralization was not able to further increase IL-12p70 production from infected DC. Whereas the central role of IL-12 in the generation of Th1 cells has long been appreciated, recently two other members of the IL-12 family, IL-23 and IL-27, were reported to play important roles in the regulation of gamma interferon (IFN-␥) production from naïve and memory T cells. A. fumigatus-infected DC were also able to express high levels of IL-23p19 and low levels of IL-27p28 at later stages of infection. According to this expression pattern, A. fumigatus-infected DC were able to prime IFN-␥ production of naïve T cells. Thus, this study on the expression of the new IL-12 family members controlling the Th1 response sheds light on a novel aspect of the contribution of DC to anti-Aspergillus immunity.

Plasmacytoid DCs (pDCs) are crucial mediators in the establishment of immunity against most viruses, given their extraordinary capacity to produce a massive quantity of type I IFN. In this study we investigate the response of pDCs to infection with EBV, a γ-herpes virus that persists with an asymptomatic infection in immunocompetent hosts, although in certain conditions it can promote development of cancers or autoimmune diseases. We show that high amounts of type I IFNs were released from isolated pDCs after exposure to EBV by a mechanism requiring TLRs and a functional autophagic machinery. We next demonstrate that EBV can infect pDCs via viral binding to MHC class II molecule HLA-DR and that pDCs express EBV-induced latency genes. Furthermore, we observe that EBV is able to induce activation but not maturation of pDCs, which correlates with an impaired TNF-α release. Accordingly, EBV-infected pDCs are unable to mount a full T-cell response, suggesting that impaired pDC maturation, combined with a concomitant EBV-mediated upregulation of the T-cell inhibitory molecules B7-H1 and ICOS-L, could represent an immune-evasion strategy promoted by the virus. These mechanisms might lead to persistence in immunocompetent hosts or to dysregulated immune responses linked to EBV-associated diseases.Keywords: EBV r Plasmacytoid DC r TLR r Type I IFN Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction EBV, a γ-herpes virus with the ability to infect the majority of human population, persists in a latent asymptomatic infection Correspondence: Dr. Eliana Marina Coccia e-mail: eliana.coccia@iss.it for the lifetime of the host. In rare cases, EBV transforming capacity might promote development of different lymphomas or nasopharyngeal and gastric carcinomas [1]. Dysregulated immune responses to EBV have also been associated with development and/or pathogenesis of several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis [2].C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 148Martina Severa et al. Eur. J. Immunol. 2013. 43: 147-158 After infection of naïve B cells, EBV normally establishes different programs of latency, where up to nine EBV-encoded proteins can be expressed: six EBV nuclear antigens (EBNAs) and three latent membrane proteins (LMP1, LMP2A, LMP2B). Two types of EBV-encoded nontranslated RNAs are also transcribed in latently infected B cells: EBERs (small nonpolyadenylated, noncoding dsRNAs, expressed in all known forms of viral latency) and BARTs (BAMH1-A rightward transcripts). Memory B cells are the long-term EBV reservoir and express either no viral genes or only LMP2A (latency 0) [1,3].EBV has elaborated many strategies to evade immune surveillance, a feature of key importance to establish a successful life-long infection. Therefore, it is not surprising that several proteins that are encoded by the EBV genome are devoted to counteract the host immune response a...