Activation of human neonatal monocyte‐derived dendritic cells by lipopolysaccharide down‐regulates birch allergen‐induced Th2 differentiation

Abstract

Epidemiological studies describe an inverse association between the level of environmental endotoxin exposure during infancy and the prevalence of allergic disease in children. To study the effect of lipopolysaccharide (LPS) and lipopeptide Pam3Cys signaling via Toll-like receptor (TLR)4 and TLR2 on dendritic cells (DC), respectively, on birch allergen-induced T cell differentiation, cord blood monocyte-derived DC were exposed to birch allergen extract alone or in combination with LPS or Pam3Cys and thereafter co-cultured with naive autologous T cells. We demonstrate that birch allergen alone induced high levels of IL-13 from neonatal T cells, whereas the production of IL-5 and IFN-c was modest. Stimulation of DC with birch allergen together with LPS but not Pam3Cys resulted in a decreased IL-13 production by T cells compared to birch allergen alone. Furthermore, birch allergen together with LPS induced increased up-regulation of activation markers expressed on the surface and production of cytokines from DC relative to stimulation with birch allergen alone. Finally, birch allergen partially suppressed both LPS-and Pam3Cys-induced DC maturation. Our results indicate that concomitant TLR4 stimulation during the initial phase of immune activation to birch allergen in infants may inhibit the development of a T helper 2-type response.

Soluble CD14 and CD83 from Human Neonatal Antigen-Presenting Cells Are Inducible by Commensal Bacteria and Suppress Allergen-Induced Human Neonatal Th2 Differentiation

“…The production of IL-5 and IFN-␥ was also measured in the cell cultures, but only very low levels of IL-5 and no IFN-␥ were induced, and increased levels were not seen after stimulation (see Fig. S6A and B in the supplemental material), as previously shown with neonatal T cells (4,27).…”

“…To investigate whether sCD14 or sCD83 might modulate neonatal birch allergen-induced T-cell responses, DC were stimulated with birch allergen extract alone or in the presence of sCD14, sCD83, or the control protein HSA and were thereafter cocultured with autologous CD4 ϩ T cells. DC were stimulated in the presence of TNF, IL-1␤, and prostaglandin E 2 , as we have previously shown that DC need to be fully mature to be able to induce birch allergeninduced T-cell expansion and differentiation (4). In order to use physiological doses of sCD14 in our culture systems, the selected concentrations (0.1 or 1 g/ml) were based on the median levels that we have recently found to be present in the circulation during infancy (cord, 0.18 g/ml; 4 months, 0.57 g/ml; 18 months, 0.97 g/ml; 3 years, 0.55 g/ml) (30).…”

“…Next, the plates were incubated with streptavidin-horseradish peroxidase (Sanquin, The Netherlands) diluted in PBS containing 0.5% bovine serum albumin. Then, 3,3Ј5,5Ј-tetramethylbenzidine (Dako, Carpinteria, CA) substrate was added to the plates, which were kept in the dark, and the reaction was stopped by the addition of 2.5 M H 2 SO 4 .…”

Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells

“…From a practical point of view, the diminished ability of the neonate to produce Th1 responses imparts vulnerability to microbial infections and the bias towards Th2 cells confers susceptibility to allergic reactions. Thus, understanding the mechanisms underlying the simultaneous Th1 unresponsiveness and robust Th2 function of the neonate represents a prerequisite for the development of pediatric vaccines and strategies against allergies [32, 33]. As there is no specific surface marker which can unambiguously distinguish Th1 from Th2 cells, we used the neonate-to-neonate T cell transfer model described above to trace primary Th1 and Th2 cells and analyzed their phenotypes upon initial contact with Ag as well as their fate upon re-exposure to Ag (Figure 2) [23].…”

Perinatal Immunotoxicity: Why Adult Exposure Assessment Fails to Predict Risk

“…This type of early-life-stage–restricted immunotoxicity appears to contribute to an increased risk of atopy and asthma. Andersson et al (2004) showed that maturation of newborn immature dendritic cells with LPS reduced the development of a T H 2-associated birch allergen response. In contrast, the lack of dendritic cell maturation from the fetal immature stage was associated with children at risk for type 1 diabetes (Skarsvik et al 2004).…”