In addition to their damaging effects, reactive oxygen intermediates exert a regulatory role on gene expression and cell apoptosis. In this study, we evaluated the effects of oxidative stress on human dendritic cells (DC), a cell type which is critical for the initiation of the immune response. For this purpose, we tested the effects of H2O2 on DC derived from adherent peripheral blood mononuclear cells cultured in the presence of granulocyte-macrophage colony-stimulating factor and IL-4. Despite a moderate increase of DC apoptosis in the presence of H2O2, we observed that H2O2 stimulated the production of IL-8 and TFN-α by DC in a dose-dependent manner. The induction of cytokine synthesis was found to depend on the oxidative properties of H2O2 as it was inhibited by the addition of catalase, and to require de novo protein synthesis as it was not observed in the presence of cycloheximide. These data suggest that DC could contribute to innate immunity through an enhanced production of inflammatory cytokines in response to oxidative stress.
The normal immune response of A/J mice against arsonate coupled to hemocyanin is characterized by a major recurrent cross-reactive Id, the CRIA. This Id is encoded by a single gene segment combination: VHidcr11-DFL16.1e-JH2 for the H chain and Vkidcr-Jk1 for the L chain. In this report, we show that lethal irradiation of A/J mice followed by reconstitution with autologous or syngeneic lymphoid cells results in loss of major CRIA Id expression in the response to arsonate. Different protocols were performed to repopulate the irradiated mice. First, lethally irradiated A/J mice were reconstituted by the transfer of syngeneic bone marrow cells. Second, A/J mice were lethally irradiated while their hind limbs were partially shielded. Third, lethally irradiated A/J mice received a transfer of syngeneic spleen cells. The three groups of mice produce high titers of antiarsonate antibodies completely devoid of CRIA DH-JH related idiotopes expression. Moreover, a lack of affinity maturation is observed in the secondary antiarsonate response of all irradiated and reconstituted mice. A transfer of syngeneic peritoneal cells or a transfer of primed T cells in irradiated and reconstituted A/J mice do not restore in a significant manner either the recurrent CRIA expression or the affinity maturation of the antiarsonate response. Our data suggest that the choice of this Id is not solely dictated by the Igh locus.
The transfer of maternal immune factors to the newborn is critical for protection from infectious disease in early life. Maternally acquired passive immunity provides protection until the infant is beyond early life's increased susceptibility to severe infections, or until active immunity is achieved following infant's primary immunization. However, as reviewed here, HIV infection alters the transfer of immune factors from HIV-infected mothers to the HIV-exposed newborns and young infants. This may relate to the immune activation in HIV-infected pregnant women, associated with the production of inflammatory cytokines at the materno-fetal interface associated with inflammatory responses in the newborn. We also summarize mother-targeting interventions to improve the health of infants born to HIV-infected women such as immunization during pregnancy and reduction of maternal inflammation. Maternal immunization offers the potential to compensate for the decreased transplacentally transferred maternal antibodies observed in HIV-exposed infants. Current data suggest reduced immunogenicity of vaccines in HIV-infected pregnant women, possibly reducing the protective impact of maternal immunization for HIV-exposed infants. Fortunately, levels of antibodies appear preserved in the breast milk of HIV-infected women, which supports the recommendation to breastfeed during antiretroviral treatment to protect HIV-exposed infants.
Granulocytes, monocytes, macrophages, and dendritic cells (DCs) represent a subgroup of leukocytes, collectively called myeloid cells. During the embryonic development of mammalians, myelopoiesis occurs in a stepwise fashion that begins in the yolk sac and ends up in the bone marrow. During this process, these early monocyte progenitors colonize various organs such as the brain, liver, skin and lungs and differentiate into resident macrophages that will self-maintain throughout life. DCs are constantly replenished from bone marrow precursors but can also arise from monocytes in inflammatory conditions. In this review, we summarize the different types of myeloid cells and discuss new insights into their early origin and development in mice and humans from fetal to adult life. We specifically focus on the function of monocytes, macrophages and DCs at these different developmental stages and on the intrinsic and environmental influences that may drive these adaptations.
Background: Maternal pertussis vaccination with Tdap vaccine is recommended to protect newborns from severe postnatal infection. HIV-exposed uninfected (HEU) newborns have a higher incidence of pertussis infection and may particularly benefit from maternal immunization. The impact of HIV infection on the quality of IgG and memory B cell (MBC) responses to Tdap vaccination in pregnant women (PW) living with HIV (PWH) is unknown.Methods: Humoral immune responses to Tdap vaccination, including IgG levels, Fc-dependent effector functions, and MBC frequencies, were measured before and after vaccination in 40 PWH and 42 HIV-uninfected PW. Placental transfer of IgG and avidity were assessed in cord blood (CB). Soluble and cellular immune activation (IA) markers were quantified at baseline.Findings: Following Tdap immunization, PWH had lower pertussis-specific IgG levels and Fc-dependent effector functions, as well as lower frequencies of MBC compared with HIV-uninfected PW. Reduced levels of maternal polyfunctional IgG and IgG avidity were transferred to HEU as compared to HIV-unexposed newborns. IgG responses to pertussis vaccination as well as maternal IgG levels and quality in HEU newborns were inversely correlated with IA in PWH.Interpretation: Maternal HIV infection is associated with defective humoral immune responses to Tdap vaccination that correlate with IA. Suboptimal transfer of maternal immunity may further increase the risk of severe pertussis infection in HEU newborns.Trial Registration: Registered on ClinicalTrials.Gov (NCT03519373).Funding: This work was supported by IRIS Fund managed by the Foundation Roi Baudouin [2017J1820690206902], Association Vésale pour la Recherche Médicale and the Medical Council of CHU Saint-Pierre.Declaration of Interest: The authors have declared that no conflict of interest exists. N.D. is a post-doctorate clinical master specialist and A.M. is Research Director at the Fonds de la Recherche Scientifique (F.R.S.-FNRS), Belgium. M.E.A. was partially supported by NIH NIAID 1U19AI14825.Ethical Approval: The study was conducted in accordance with the Helsinki Declaration of the World Medical Association, approved by the local ethic committee (#B076201630448). Written informed consent of all participating subjects was received prior to participation.
Abstract N-acetyl-l-cysteine (NAC) is an antioxidant molecule endowed with immunomodulatory properties. To investigate the effect of NAC on the induction phase of T cell responses, we analyzed its action on human dendritic cells (DC) derived from adherent PBMC cultured with IL-4 and granulocyte-macrophage CSF. We first found that NAC inhibited the constitutive as well as the LPS-induced activity of the transcription factor NF-κB. In parallel, NAC was shown to down-regulate the production of cytokines by DC as well as their surface expression of HLA-DR, CD86 (B7-2), and CD40 molecules both at the basal state and upon LPS activation. NAC also inhibited DC responses induced by CD40 engagement. The inhibitory effects of NAC were not due to nonspecific toxicity as neither the viability of DC nor their mannose receptor-mediated endocytosis were modified by NAC. Finally, we found that the addition of NAC to MLR between naive T cells and allogeneic DC resulted in a profound inhibition of alloreactive responses, which could be attributed to a defect of DC as APC-independent T cell responses were not inhibited by NAC. Altogether, our results suggest that NAC might impair the generation of primary immune responses in humans through its inhibitory action on DC.
Abstract Interleukin (IL)‐23 is a heterodimeric cytokine of the IL‐12 family. Human IL‐23 is known to induce interferon (IFN)‐γ production and proliferation in T cells, preferentially in the CD45RO + memory subset. Yet, its role in the differentiation of human naive T cells remains largely unknown. We investigated the effect of recombinant human (rh)IL‐23 on cord blood CD4 + and CD8 + T cells during polyclonal activation. The IL‐23 receptor complex was not detectable in resting naive T cells. Nevertheless, both IL‐23 receptor subunits, IL‐12Rβ1 and IL‐23R, were rapidly induced after activation in both naive CD4 + and CD8 + T cells. In both cell types, rhIL‐23 enhanced IFN‐γ production. This effect was demonstrable as early as 2 days after activation, illustrating that a functional IL‐23 receptor is rapidly induced in naive T cells upon activation. In naive CD8 + T cells, rhIL‐23 specifically induced the secretion of IL‐17, a pro‐inflammatory cytokine. Moreover, rhIL‐23 significantly increased the production of IL‐10 in both naive CD4 + and CD8 + T cells. IL‐17 and IL‐10 levels were not affected by the addition of rhIL‐12. We conclude that IL‐23 induces a specific cytokine profile, remarkably distinct from IL‐12, in activated human naive T cells.
Bordetella pertussis toxin (PTX), a key component of acellular pertussis vaccines, is known to be endowed with adjuvant properties. In experiments designed to get insights into the interactions between PTX and circulating immune cells, we first observed that addition of PTX to adult whole blood induced the release of IL-12 and TNF-alpha as well as maturation of myeloid dendritic cells (DC). These effects were still present with a toxin mutant devoid of ADP-ribosyltransferase activity but not with a formaldehyde-inactivated toxin. These findings indicate that cytokine production and DC maturation require the intact structure of PTX but not its enzymatic activity. Secondly, studies on DC generated in vitro by culturing monocytes with IL-4 and GM-CSF showed that PTX directly stimulates MHC class II and costimulatory molecules up-regulation, cytokine synthesis and NF-kappa B activation. Finally, comparison of data obtained in adult vs. cord blood revealed deficient responses of neonatal DC to PTX. These data suggest new applications of PTX and PTX mutants as vaccine adjuvants.
