The immune response is a tightly regulated process which normally results in protection from infection and tolerance of innocuous environmental antigens. However, in allergy and asthma, the activated immune response results in a chronic pro-inflammatory state characterized by T cell Th2 polarization to normally well-tolerated antigens resulting in tissue inflammation and tissue remodeling. Dendritic cells (DCs) are essential for inducing activation and differentiation of effector CD4+ and CD8+ T cells in response to antigens, and it is well established that these cells play a pivotal role in the initiation and maintenance phase of inflammatory responses. However, the molecular basis for aberrant DC activation within inflamed tissues is poorly defined. The hypothesis to be tested in this proposal is that pattern recognition receptor (PRR) activation in the context of histamine receptor (HR) stimulation skews the DC activation program resulting in aberrant T cell polarization. Human-derived DCs and T cells from humans will be utilized in order to ensure the results obtained are relevant in vivo.This project is a significant leap forward as it combines multiple, clinically relevant, triggers of DC activation in a co-ordinated research program, which will ultimately result in the identification of new therapeutic targets for allergy and asthma patients. The original feature of this proposal relates to the elucidation of the key molecular checkpoints intersecting HR and PRR pathways, in myeloid and plasmacytoid DCs from allergy and asthmatic patients. SIAF is well placed to perform these studies as SIAF members have well-established track records in elucidating novel immunological mechanisms in allergy and asthma. The public health implications of this proposal are immense as development of novel DC modifying compounds allows clinicians to target a range of inflammatory diseases such as asthma, allergy, autoimmune disorders and inflammatory bowel disease (IBD).