Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells

Aksoy, Ezra; Albarani, Valentina; Nguyen, Muriel; Laes, Jean-François; Ruelle, Jean-Louis; Wit, Dominique De; Willems, Fabienne; Goldman, Michel; Goriely, Stanislas

doi:10.1182/blood-2006-06-027862

Cited by 84 publications

(88 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, deficient IRF-3 activity in lipopolysaccharidestimulated cord blood monocyte-derived DC is associated with a reduced ability to produce IFN-b, IL-12p70 and IFN-inducible chemokines [25]. We suggest that defective IRF-3 activation in cord blood monocytederived DC and impaired IRF-7 translocation in cord blood pDC represent two key molecular signatures underlying the immaturity of neonatal DC.…”

Section: Discussionmentioning

confidence: 79%

Interferon regulatory factor 7‐mediated responses are defective in cord blood plasmacytoid dendritic cells

et al. 2008

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 79%

Interferon regulatory factor 7‐mediated responses are defective in cord blood plasmacytoid dendritic cells

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although type I IFN function is not required for the adjuvant activity of GVI3000 in adult mice (51), it is an indicator of GVI3000 RNA replication and of a robust innate immune response. The observation that neonatal mice had adult-level type I IFN responses to GVI3000 indicates that the adjuvant may overcome the impairment in type I IFN induction observed in newborn cord blood (76,77). Additionally, the type I IFN response was systemic, peaking at 12 h postimmunization and falling to the background level by 36 h. This demonstrates that the GVI3000-mediated inflammatory response is transient, reducing any chance of prolonged inflammation or toxicity.…”

Section: Discussionmentioning

confidence: 93%

An Alphavirus-Based Adjuvant Enhances Serum and Mucosal Antibodies, T Cells, and Protective Immunity to Influenza Virus in Neonatal Mice

Khalil

Tonkin

Snead

et al. 2014

J Virol

View full text Add to dashboard Cite

Neonatal immune responses to infection and vaccination are biased toward T H 2 at the cost of proinflammatory T H 1 responses needed to combat intracellular pathogens. However, upon appropriate stimulation, the neonatal immune system can induce adult-like T H 1 responses. Here we report that a new class of vaccine adjuvant is especially well suited to enhance early life immunity. The GVI3000 adjuvant is a safe, nonpropagating, truncated derivative of Venezuelan equine encephalitis virus that targets dendritic cells (DCs) in the draining lymph node (DLN) and produces intracellular viral RNA without propagating to other cells. RNA synthesis strongly activates the innate immune response so that in adult animals, codelivery of soluble protein antigens induces robust humoral, cellular, and mucosal responses. The adjuvant properties of GVI3000 were tested in a neonatal BALB/c mouse model using inactivated influenza virus (iFlu). After a single immunization, mice immunized with iFlu with the GVI3000 adjuvant (GVI3000-adjuvanted iFlu) had significantly higher and sustained influenza virus-specific IgG antibodies, mainly IgG2a (T H 1), compared to the mice immunized with antigen only. GVI3000 significantly increased antigen-specific CD4؉ and CD8 ؉ T cells, primed mucosal immune responses, and enhanced protection from lethal challenge. As seen in adult mice, the GVI3000 adjuvant increased the DC population in the DLNs, caused activation and maturation of DCs, and induced proinflammatory cytokines and chemokines in the DLNs soon after immunization, including gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), granulocyte colony-stimulating factor (G-CSF), and interleukin 6 (IL-6). In summary, the GVI3000 adjuvant induced an adult-like adjuvant effect with an influenza vaccine and has the potential to improve the immunogenicity and protective efficacy of new and existing neonatal vaccines. IMPORTANCEThe suboptimal immune responses in early life constitute a significant challenge for vaccine design. Here we report that a new class of adjuvant is safe and effective for early life immunization and demonstrate its ability to significantly improve the protective efficacy of an inactivated influenza virus vaccine in a neonatal mouse model. The GVI3000 adjuvant delivers a truncated, self-replicating viral RNA into dendritic cells in the draining lymph node. Intracellular RNA replication activates a strong innate immune response that significantly enhances adaptive antibody and cellular immune responses to codelivered antigens. A significant increase in protection results from a single immunization. Importantly, this adjuvant also primed a mucosal IgA response, which is likely to be critical for protection during many early life infections.

show abstract

“…In neonate DCs, similar to our study using adult monocyte-derived DCs, selective deficiency in IL-12p70 production resulted from impaired IL-12p35 transcription upon activation. Goldman and coworkers have identified defective nucleosome remodeling (at the SP-1 site) of the IL-12p35 promoter and lack of IRF-3 phosphorylation as mechanisms that may account for impaired IL-12p35 transcription in newborn-derived DCs (45,46). However, IFN-γ treatment of neonate DCs can restore IL-12p35 transcription and IL-12p70 synthesis.…”

Section: Figurementioning

confidence: 99%

IL-12p70–producing patient DC vaccine elicits Tc1-polarized immunity

Carreño¹,

Becker-Hapak²,

Huang³

et al. 2013

J. Clin. Invest.

144

141

View full text Add to dashboard Cite

Background. Systemic administration of IL-12p70 has demonstrated clinical activity in cancer patients, but doselimiting toxicities have hindered its incorporation in vaccine formulations. Here, we report on the immunological and clinical outcomes upon vaccination with CD40L/IFN-γ-matured, IL-12p70-producing DCs.Methods. 7 HLA-A*0201 + newly diagnosed stage IV melanoma patients were immunized against the gp100 melanoma antigen using autologous peptide-pulsed, CD40L/IFN-γ-matured DCs. PBMCs were taken weekly for immune monitoring by tetramer analysis and functional assays. CT imaging was performed at baseline, week 9, and week 18 for clinical assessment using RECIST.Results. 6 of 7 treated patients developed sustained T cell immunity to all 3 melanoma gp100 antigen-derived peptides. 3 of the 6 immunological responders developed confirmed clinical responses (1 complete remission >4 years, 2 partial response). Importantly, DC vaccine-derived IL-12p70 levels positively correlated with time to progression (P = 0.019, log-rank), as did T-cytotoxic 1 (Tc1) immunity, as assessed by IFN-γ/IL-13 and IFN-γ/IL-5 ratios (P = 0.035 and P = 0.030, respectively, log-rank). In contrast, a pathway-specific defect in IL-12p35 transcription was identified upon CD40L/IFN-γ activation in clinical nonresponder patient DCs, and gp100-specific T cells from these patients displayed a Tc2 phenotype. Incorporation of TLR3 and TLR8 agonists into the CD40L/IFN-γ activation protocol corrected the IL-12p70 production defect in DCs derived from clinical nonresponder patients.Conclusion. These findings underscore the essential role of IL-12p70 in the development of therapeutic type 1 antigen-specific CD8 + T cell immunity in humans with cancer.

show abstract

Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells

Cited by 84 publications

References 44 publications

Interferon regulatory factor 7‐mediated responses are defective in cord blood plasmacytoid dendritic cells

Interferon regulatory factor 7‐mediated responses are defective in cord blood plasmacytoid dendritic cells

An Alphavirus-Based Adjuvant Enhances Serum and Mucosal Antibodies, T Cells, and Protective Immunity to Influenza Virus in Neonatal Mice

IL-12p70–producing patient DC vaccine elicits Tc1-polarized immunity

Contact Info

Product

Resources

About