ABSTRACT
Studies examining the role of programmed death 1 (PD-1) ligand 2 (PD-L2)/PD-1 in asthma have yielded conflicting results. To clarify its role, we examined the PD-L2 expression in biopsies from human asthmatics and the lungs of aeroallergen-treated mice. PD-L2 expression in bronchial biopsies correlated with the severity of asthma. In mice, allergen exposure increased PD-L2 expression on pulmonary myeloid dendritic cells (DCs), and PD-L2 blockade diminished allergen-induced airway hyperresponsiveness (AHR). By contrast, PD-1 blockade had no impact, suggesting that PD-L2 promotes AHR in a PD-1-independent manner. Decreased AHR was associated with enhanced serum interleukin (IL)-12 p40, and in vitro stimulation of DCs with allergen and PD-L2-Fc reduced IL-12 p70 production, suggesting that PD-L2 inhibits allergen-driven IL-12 production. In our model, IL-12 did not diminish T helper type 2 responses but rather directly antagonized IL-13-inducible gene expression, highlighting a novel role for IL-12 in regulation of IL-13 signaling. Thus, allergen-driven enhancement of PD-L2 signaling through a PD-1-independent mechanism limits IL-12 secretion, exacerbating AHR.
Subject(s)
Asthma/immunology , Asthma/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Interleukin-12/biosynthesis , Programmed Cell Death 1 Ligand 2 Protein/metabolism , Allergens/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/immunology , Asthma/drug therapy , Asthma/genetics , Bronchial Hyperreactivity/immunology , Bronchial Hyperreactivity/metabolism , Gene Expression Regulation/drug effects , Immunoglobulin G/immunology , Interleukin-12 Subunit p40/metabolism , Interleukin-13/metabolism , Interleukin-13/pharmacology , Male , Mice , Mucus/metabolism , Myeloid Cells/immunology , Myeloid Cells/metabolism , Programmed Cell Death 1 Ligand 2 Protein/agonists , Programmed Cell Death 1 Ligand 2 Protein/antagonists & inhibitors , Signal Transduction/drug effectsABSTRACT
Chemoreception is a principle modality by which organisms gain information from their environment, and extensive variation in odor-mediated behavior has been documented within and among species. To examine the mechanisms by which sensory systems mediate these responses, we ask to what extent variation in Drosophila melanogaster odorant receptor genes contributes to variation in odor-mediated behavior. Significant differences in behavioral responses to structurally similar odorants, methyl hexanoate and ethyl hexanoate, were found in a natural population. Polymorphisms in 3 genomic regions (Or22a/Or22b, Or35a, and Or47a) were identified and associated with variation in behavior to these esters. Overall similarity in association profiles for both odorants was observed, except for Or47a in which polymorphisms were associated solely with variation in responses to ethyl hexanoate. Our analyses were then extended to examine polymorphisms in 3 odorant receptors previously reported to contribute to variation in olfactory behavior for the chemically distinct odorants benzaldehyde and acetophenone. Two Or10a polymorphisms were associated with variation in response to ethyl hexanoate. Finally, differences in Or35a and Or47a expression were associated with variation in responses to ethyl hexanoate. These results demonstrate that the genetic variation at the peripheral sensory stage plays a role in mediating differences in odor-mediated behavior.
