Background: Invariant natural killer T (iNKT) cells play a beneficial role during experimental influenza A virus (IAV) infection.Results: iNKT cells produce IL-22 during infection, and IL-22 prevents the IAV-triggered cell death of pulmonary epithelium. Conclusion: IL-22 produced by iNKT cells might be important during IAV infection.Significance: Understanding how iNKT cells function during IAV infection might be instrumental to control IAV-associated pathogenesis.

No abstract

IL-27 is a heterodimeric cytokine composed of EBV-induced gene 3 and p28. Produced by dendritic cells (DCs) in response to TLR ligands, IL-27 recently emerged as a key regulator of inflammatory responses. In this study, we first demonstrate that Toll/IL-1R-containing adaptor inducing IFN-β and its associated IFN regulatory factor (IRF) 3 transcription factor are critically involved in IL-27p28 expression in mouse DCs stimulated by TLR ligands. We then show that IL-27 serum levels are dramatically reduced in IRF3−/− upon LPS injection, indicating a critical role for IRF3 in TLR4-mediated IL-27 production in vivo. We identified an IRF3-binding site within the IL-27p28 promoter region which is required for IL-27p28 gene activation in reporter gene assays. In human DCs, IL-27p28 mRNA was preferentially induced by Toll/IL-1R-containing adaptor inducing IFN-β-coupled TLR ligands and following CMV infection. Furthermore, chromatin immunoprecipitation studies demonstrate that IRF3 is recruited to the endogenous p28 promoter in TLR4-stimulated human DCs. We conclude that IRF3 activation is a master switch for IL-27 synthesis.

Influenza A virus (IAV) infection results in a highly contagious respiratory illness leading to substantial morbidity and occasionally death. In this report, we assessed the in vivo physiological contribution of invariant NKT (iNKT) lymphocytes, a subset of lipid-reactive αβ T lymphocytes, on the host response and viral pathogenesis using a virulent, mouse-adapted, IAV H3N2 strain. Upon infection with a lethal dose of IAV, iNKT cells become activated in the lungs and bronchoalveolar space to become rapidly anergic to further restimulation. Relative to wild-type animals, C57BL/6 mice deficient in iNKT cells (Jα18−/− mice) developed a more severe bronchopneumonia and had an accelerated fatal outcome, a phenomenon reversed by the adoptive transfer of NKT cells prior to infection. The enhanced pathology in Jα18−/− animals was not associated with either reduced or delayed viral clearance in the lungs or with a defective local NK cell response. In marked contrast, Jα18−/− mice displayed a dramatically reduced IAV-specific CD8+ T cell response in the lungs and in lung-draining mediastinal lymph nodes. We further show that this defective CD8+ T cell response correlates with an altered accumulation and maturation of pulmonary CD103+, but not CD11bhigh, dendritic cells in the mediastinal lymph nodes. Taken together, these findings point to a role for iNKT cells in the control of pneumonia as well as in the development of the CD8+ T cell response during the early stage of acute IAV H3N2 infection.

Plasmacytoid dendritic cells (pDC) are specialized in massive production of type I interferons (IFN) upon viral infections. Activation of IFN regulatory factor (IRF)-7 is critically required for the synthesis of type I IFN in pDC. IRF-7 is highly expressed by resting pDC and translocates into the nucleus to initiate type I IFN transcription. In a previous work, we observed an impaired IFN-a production in enriched cord blood pDC following a TLR9 stimulation using CpG oligonucleotides. Herein, we show that highly purified pDC from cord blood exhibit a profound defect in their capacity to produce IFN-a/b in response to TLR9 as well as to TLR7 ligation or human CMV or HSV-1 exposure. Microarray experiments indicate that expression of the majority of type I IFN subtypes induced by a TLR7 agonist is reduced in cord blood pDC. We next demonstrated a reduced nuclear translocation of IRF-7 in cord blood pDC following CpG and HSV stimulation as compared to adult pDC. We conclude that impaired IRF-7 translocation in cord blood pDC is associated with defective expression of type I IFN genes. Our data provide a molecular understanding for the decreased ability of cord blood pDC to produce type I IFN upon viral stimulation.

These data imply a new function for pulmonary CD103(+) DCs in mucosal activation of iNKT cells and establish a critical role for both IFN-γ and IL-17 signalling pathways in mediating the innate immune response to S. pneumoniae.

Following congenital human CMV (HCMV) infection, 15-20% of infected newborns develop severe health problems whereas infection in immunocompetent adults rarely causes illness. The immaturity of neonatal antigen presenting cells could play a pivotal role in this susceptibility. Neonatal myeloid DC were shown to be deficient in IFN-b and IL-12 synthesis in response to TLR triggering. We studied the response of cord and adult bloodderived myeloid DC to HCMV infection. Neonatal and adult DC were equally susceptible to in vitro HCMV infection. Among immunomodulatory cytokines, IL-12, IFN-b and IFN-k1 were produced at lower levels by neonatal as compared with adult DC. In contrast, neonatal and adult DC produced similar levels of IFN-a and IFN-inducible genes. Microarray analysis indicated that among the more than thousand genes up-or down-regulated by HCMV infection of myeloid DC, 88 were differently regulated between adult and neonatal DC. We conclude that neonatal and adult DC trigger a partly different response to HCMV infection. The deficient IL-12 and mature IFN-a production by neonatal DC exposed to HCMV are likely to influence the quality of the T lymphocyte response to HCMV infection in early life.

Measles is a highly contagious childhood disease associated with an immunological paradox: although a strong virus-specific immune response results in virus clearance and the establishment of a life-long immunity, measles infection is followed by an acute and profound immunosuppression leading to an increased susceptibility to secondary infections and high infant mortality. In certain cases, measles is followed by fatal neurological complications. To elucidate measles immunopathology, we have analyzed the immune response to measles virus in mice transgenic for the measles virus receptor, human CD150. These animals are highly susceptible to intranasal infection with wild-type measles strains. Similarly to what has been observed in children with measles, infection of suckling transgenic mice leads to a robust activation of both T and B lymphocytes, generation of virus-specific cytotoxic T cells and antibody responses. Interestingly, Foxp3+CD25+CD4+ regulatory T cells are highly enriched following infection, both in the periphery and in the brain, where the virus intensively replicates. Although specific anti-viral responses develop in spite of increased frequency of regulatory T cells, the capability of T lymphocytes to respond to virus-unrelated antigens was strongly suppressed. Infected adult CD150 transgenic mice crossed in an interferon receptor type I-deficient background develop generalized immunosuppression with an increased frequency of CD4+CD25+Foxp3+ T cells and strong reduction of the hypersensitivity response. These results show that measles virus affects regulatory T-cell homeostasis and suggest that an interplay between virus-specific effector responses and regulatory T cells plays an important role in measles immunopathogenesis. A better understanding of the balance between measles-induced effector and regulatory T cells, both in the periphery and in the brain, may be of critical importance in the design of novel approaches for the prevention and treatment of measles pathology.