Abstract
BackgroundTrained immunity is the ability of the innate immune system to form immune memory responses to provide support the formation of appropriate adaptive responses. Allergic airways disease (AAD) is a maladapted immune response to allergens, initiated and maintained by the type 2 (T2) inflammatory pathway. It is predicated by the elaboration of cytokines IL-4 and IL-13 and follows activation of the STAT6 transcription factor.ObjectiveTo investigate the role of trained immunity in mucosal immune responses following neonatal vaccination with the STAT6 inhibitory peptide (STAT6-IP), in preventing the development of ragweed-induced AAD.MethodsWe demonstrate that transfer of CD4+ T cells or dendritic cells (DC) from STAT6-IP vaccinated wild-type BALB/c mice to naïve mice, that were subsequently chronically exposed to sensitizing doses of ragweed allergen, is sufficient to prevent development of T2 responses in recipients.ResultsOur results demonstrate significant reductions in; airways hyperresponsiveness (AHR); ragweed-specific IgE; pulmonary inflammation; T2 cytokines; and inflammatory gene expressions in recipient mice. Expression of IDO, TGFβ and T regulatory cells were all significantly increased. Anti-TGFβ treatment during the ragweed sensitization phase re-constituted the pro-inflammatory T2 immune response. We show that tolerance can be attained via DC trained in the STAT6-IP-mediated tolerant milieu. This effect is not restricted to a particular allergen and does not require antigen-mediated T cell activation prior to transfer.ConclusionAdoptive transfer experiments suggest that STAT6-IP treatment trains dendritic and cells to mediate tolerant immunity to chronic ragweed exposure in the airways. This indicates that early transient STAT6-inhibition constitutes an effective immunomodulatory airways allergy preventative strategy.
Highlights
Environmental stimuli immunomodulates mucosal responses resulting in changes to lifetime risk of the development of allergic airways disease (AAD) [1,2,3]
The STAT6-IP differs from the STAT6-control peptide (CP) via a single substitution of the phosphotyrosine for a phenylalanine [17]. CD4+ T cells from neonatal STAT-6-IP (IP-T cells) exposed mice were harvested from spleen and transferred into naïve mice to determine if the observed AAD protective effect was transferrable by these cells
IP-T cell recipient immune response was compared with CP-T cell recipient (CP-T), allergic mice and naïve (PBS) mice
Summary
Environmental stimuli immunomodulates mucosal responses resulting in changes to lifetime risk of the development of allergic airways disease (AAD) [1,2,3]. Fetal and neonatal immune responses differ significantly than in children and adults. Both the innate and adaptive immune systems are quite impaired in neonates. Allergic airways disease (AAD) is a maladapted immune response to allergens, initiated and maintained by the type 2 (T2) inflammatory pathway. It is predicated by the elaboration of cytokines IL-4 and IL-13 and follows activation of the STAT6 transcription factor
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