Article

Acquisition of Adult-Like TLR4 and TLR9 Responses during the First Year of Life

Ludwig-Maximilians-Universität München, Germany
PLoS ONE (Impact Factor: 3.23). 04/2010; 5(4):e10407. DOI: 10.1371/journal.pone.0010407
Source: PubMed

ABSTRACT Characteristics of the human neonatal immune system are thought to be responsible for heightened susceptibility to infectious pathogens and poor responses to vaccine antigens. Using cord blood as a source of immune cells, many reports indicate that the response of neonatal monocytes and dendritic cells (DC) to Toll-like receptor (TLR) agonists differs significantly from that of adult cells. Herein, we analyzed the evolution of these responses within the first year of life.
Blood samples from children (0, 3, 6, 9, 12 month old) and healthy adults were stimulated ex vivo with bacterial lipopolysaccharide (LPS, TLR4 agonist) or CpG oligonucleotides (TLR9 agonist). We determined phenotypic maturation of monocytes, myeloid (m) and plasmacytoid (p) DC and production of cytokines in the culture supernatants. We observed that surface expression of CD80 and HLA-DR reaches adult levels within the first 3 months of life for mDCs and 6-9 months of life for monocytes and pDCs. In response to LPS, production of TNF-alpha, IP-10 and IL-12p70 reached adult levels between 6-9 months of life. In response to CpG stimulation, production of type I IFN-dependent chemokines (IP-10 and CXCL9) gradually increased with age but was still limited in 1-year old infants as compared to adult controls. Finally, cord blood samples stimulated with CpG ODN produced large amounts of IL-6, IL-8, IL-1beta and IL-10, a situation that was not observed for 3 month-old infants.
The first year of life represents a critical period during which adult-like levels of TLR responses are reached for most but not all cytokine responses.

Download full-text

Full-text

Available from: Elke Leuridan, Sep 02, 2015
0 Followers
 · 
158 Views
 · 
89 Downloads
  • Source
    • "Several studies have shown that there are high levels of the immunosuppressive cytokine IL-10 in cord blood (CB; De Wit et al., 2004; Belderbos et al., 2009; Nguyen et al., 2010). IL-10 can be produced by most cell types of the immune system, including antigen presenting cells (APCs), granulocytes, and Th1, Th2 and many regulatory T cell subsets. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human newborns and infants are bombarded with multiple pathogens on leaving the sterile intra-uterine environment, and yet have suboptimal innate immunity and limited immunological memory, thus leading to increased susceptibility to infections in early life. They are thus the target age group for a host of vaccines against common bacterial and viral pathogens. They are also the target group for many vaccines in development, including those against tuberculosis (TB), malaria, and HIV infection. However, neonatal and infant responses too many vaccines are suboptimal, and in the case of the polysaccharide vaccines, it has been necessary to develop the alternative conjugated formulations in order to induce immunity in early life. Immunoregulatory factors are an intrinsic component of natural immunity necessary to dampen or control immune responses, with the caveat that they may also decrease immunity to infections or lead to chronic infection. This review explores the key immunoregulatory factors at play in early life, with a particular emphasis on regulatory T cells (Tregs). It goes on to explore the role that Tregs play in limiting vaccine immunogenicity, and describes animal and human studies in which Tregs have been depleted in order to enhance vaccine responses. A deeper understanding of the role that Tregs play in limiting or controlling vaccine-induced immunity would provide strategies to improve vaccine immunogenicity in this critical age group. New adjuvants and drugs are being developed that can transiently suppress Treg function, and their use as part of human vaccination strategies against infections is becoming a real prospect for the future.
    Frontiers in Microbiology 09/2014; 5:477. DOI:10.3389/fmicb.2014.00477 · 3.94 Impact Factor
  • Source
    • "After TLR stimulation, production of IL-12p70 is still below adult levels in 12 years old children whereas synthesis of IL-23, IL-6, and IL-10 dominates in term infants (78, 95, 96). Interestingly, production of IL-23, IL-6, and IL-10 declines over the first few years of life, while secretion of pro-inflammatory cytokines TNFα and IL-1β gradually increases with age (97, 98). These findings indicate that cDCs have a reduced ability to produce Th1-supporting cytokines, which corresponds to increased risk of infection with intracellular pathogens such as Listeria monocytogenes, M. tuberculosis, and HSV in early life. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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 (BM). 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 BM 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.
    Frontiers in Immunology 09/2014; 5:423. DOI:10.3389/fimmu.2014.00423
  • Source
    • "Numerous studies have reported the reduced in vitro responses of human cord blood pDCs to TLR7 or TLR9 ligands [66-70], suggesting the existence of intrinsic pDC limitations persisting until at least 6-12 months of age [68]. Functionally, an inverse correlation was reported between circulating pDC numbers and the clinical severity of lower respiratory tract infections in infants and young children [71]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: INFANT MORTALITY FROM VIRAL INFECTION REMAINS A MAJOR GLOBAL HEALTH CONCERN: viruses causing acute infections in immunologically mature hosts often follow a more severe course in early life, with prolonged or persistent viral replication. Similarly, the WE strain of lymphocytic choriomeningitis virus (LCMV-WE) causes acute self-limiting infection in adult mice but follows a protracted course in infant animals, in which LCMV-specific CD8(+) T cells fail to expand and control infection. By disrupting type I IFNs signaling in adult mice or providing IFN-α supplementation to infant mice, we show here that the impaired early life T cell responses and viral control result from limited early type I IFN responses. We postulated that plasmacytoid dendritic cells (pDC), which have been identified as one major source of immediate-early IFN-I, may not exert adult-like function in vivo in the early life microenvironment. We tested this hypothesis by studying pDC functions in vivo during LCMV infection and identified a coordinated downregulation of infant pDC maturation, activation and function: despite an adult-like in vitro activation capacity of infant pDCs, the expression of the E2-2 pDC master regulator (and of critical downstream antiviral genes such as MyD88, TLR7/TLR9, NF-κB, IRF7 and IRF8) is downregulated in vivo at baseline and during LCMV infection. A similar pattern was observed in response to ssRNA polyU, a model ligand of the TLR7 viral sensor. This suggests that the limited T cell-mediated defense against early life viral infections is largely attributable to / regulated by infant pDC responses and provides incentives for novel strategies to supplement or stimulate immediate-early IFN-α responses.
    PLoS ONE 12/2013; 8(12):e85302. DOI:10.1371/journal.pone.0085302 · 3.23 Impact Factor
Show more