Background-IL-9-secreting (T H 9) T cells are thought to represent a distinct T-cell subset. However, evidence for their functionality in disease is uncertain.

Inhaled HDM challenge induces a classical Th2 inflammatory mediator profile in the BAL and lung. These data are important for studies determining the efficacy of novel treatment strategies for allergic airways disease.

Background Induction of endogenous regulatory T cells (Tregs) represents an exciting new potential modality for treating allergic diseases such as asthma. Tregs have been implicated in the regulation of asthma but the anatomic location where they exert their regulatory function, and the mechanisms controlling their migration necessary for their suppressive function in asthma are not known. Understanding these aspects of Treg biology will be important for harnessing their power in the clinic. Objective To determine the anatomic location where Tregs exert their regulatory function in the sensitization and effector phases of allergic asthma, and to determine the chemokine receptors that control the migration of Tregs to these sites in vivo in mice and in humans. Methods The clinical efficacy and the anatomic location of adoptively transferred chemokine receptor-deficient CD4+CD25+ Foxp3+ Tregs was determined in the sensitization and effector phases of allergic airway inflammation in mice. The chemokine receptor expression profile was determined on Tregs recruited into the human airway following bronchoscopic segmental allergen challenge of subjects with asthma. Results We show that CCR7, but not CCR4, is required on Tregs to suppress allergic airway inflammation during the sensitization phase. In contrast, CCR4, but not CCR7, is required on Tregs to suppress allergic airway inflammation during the effector phase. Consistent with our murine studies, humans with allergic asthma had an increase in CCR4 expressing functional Tregs in the lung following segmental allergen challenge. Conclusion The location of Treg function differs during allergic sensitization and during allergen-induced recall responses in the lung, and that this differential localization is critically dependent on differential chemokine function.

Innate immune responses to allergens by airway epithelial cells (AECs) help initiate and propagate the adaptive immune response associated with allergic airway inflammation in asthma. Activation of the transcription factor NF-κB in AECs by allergens or secondary mediators via G-protein-coupled receptors (GPCRs) is an important component of this multifaceted inflammatory cascade. Members of the caspase recruitment domain (CARD) family of proteins display tissue specific expression and help mediate NF-κB activity in response to numerous stimuli. We have previously shown that CARMA3 is specifically expressed in AECs and mediates NF-κB activation in these cells in response to stimulation with the GPCR agonist lysophosphatidic acid (LPA). Here we demonstrate that reduced levels of CARMA3 in normal human bronchial epithelial cells decreases the production of pro-asthmatic mediators in response to a panel of asthma-relevant GPCR ligands such as LPA, adenosine tri-phosphate, and allergens that activate GPCRs such as Alternaria alternata and house dust mite. We then show that genetically modified mice with CARMA3-deficient AECs have reduced airway eosinophilia and pro-inflammatory cytokine production in a murine model of allergic airway inflammation. In addition, we demonstrate that these mice have impaired dendritic cell maturation in the lung and that dendritic cells from mice with CARMA3-deficient AECs have impaired antigen processing. In conclusion, we show that AEC CARMA3 helps mediate allergic airway inflammation, and that CARMA3 is a critical signaling molecule bridging the innate and adaptive immune responses in the lung.