Defective aeroallergen surveillance by airway mucosal dendritic cells as a determinant of risk for persistent airways hyper-responsiveness in experimental asthma.

A hallmark of atopic asthma is development of chronic airways hyper-responsiveness (AHR) that persists in the face of ongoing exposure to perennial aeroallergens. We investigated underlying mechanisms in sensitized rats focusing on a strain expressing the high-allergen-responder phenotype characteristic of human atopic asthmatics, and find that their high susceptibility to aeroallergen-induced persistent AHR is associated with deficiencies in the immunoregulatory and mucosal trafficking properties of inducible T-regulatory cells (iTregs). Counterintuitively, AHR susceptibility was inversely related to aeroallergen exposure level, high exposures conferring protection. We demonstrate that underlying this AHR-susceptible phenotype is reduced capacity of airway mucosal dendritic cells (AMDCs) for allergen sampling in vivo; this defect is microenvironmentally acquired, as allergen uptake by these cells in vitro is normal. Moreover, intranasal transfer of in vitro aeroallergen-loaded AMDC from naïve animals into AHR-susceptible animals during prolonged aerosol challenge markedly boosts subsequent accumulation of iTregs in the airway mucosa and rapidly resolves their chronic AHR, suggesting that compromised antigen surveillance by AMDC resulting in defective functional programming of iTreg may be causally related to AHR susceptibility.

T-cell activation genes differentially expressed at birth in CD4+ T-cells from children who develop IgE food allergy.

BACKGROUND: Presymptomatic immaturity in neonatal T-cell function is a consistent antecedent of allergic disease, including reduced responsiveness to polyclonal activation. METHODS: To elucidate the underlying mechanisms, we examined for differences in T-cell gene expression in longitudinal samples collected at birth and at 1 year of age in children with (n = 30) and without IgE-mediated food allergy (n = 30). We employed a low-level soluble anti-CD3 stimulus to activate the T-cell receptor (TCR) and surveyed gene expression by DNA microarray in purified CD4(+) T-cells. Allergen-specific responses were assessed in parallel functional studies. RESULTS: At birth, the allergic group showed a reduced number of genes up regulated in response to anti-CD3 treatment on the microarray and a reduced lympho proliferative capacity, suggesting clear differences in T-cell signalling pathways. Polymerase chain reaction (PCR) validation of candidate genes confirmed significantly lower expression of a number of genes in the allergic group including RELB, NFKB2, LIF and FAS. By 12 months of age, there were marked changes in the anti-CD3 response in all infants, culminating in upregulation of cytokine genes (IL-5, IL-13, IL-17 and IL-22). Neonatal differences were no longer apparent. Instead, the allergic group, all symptomatic by this age, showed differential expression of T-cell lineage pathways including GATA-3, MAL and FcER1 in unstimulated T-cells. Allergen stimulation induced significantly higher cytokines production (IL-5, IL-13 and IFNγ) in the allergic group. CONCLUSION: Although transient, suboptimal neonatal T-cell activation pathways that signal through the NF-κB complex may affect the developmental transition of T-cell phenotypes in the periphery shortly after birth and may increase the risk of food allergy.