Defining the impact of dendritic cells on regulatory T cell induction and stability during asthma

Chronic inflammation that underlies asthma likely modulates both induction of, and resistance to, tolerogenic mechanisms. Further, modified dendritic cell (DC) and regulatory T cell (Treg) activation and function has been reported in chronic inflammatory disease settings, but has not yet been addressed in asthma. Building on ongoing collaboration with GlaxoSmithKline (GSK), this project will define how asthma influences activation of, and dialogue between, DCs and Tregs, using patient samples and murine models and a combination of in vivo, ex vivo and in vitro experimental approaches. Taking advantage of collaboration with the Manchester Allergy, Respiratory and Thoracic Surgery biobank (ManARTS), we will obtain blood, sputum and lung resection tissue from asthmatic donors to generate a high-level understanding of DC, Treg and effector T cell (Teff) subset proportions and activation states during asthma, using multi-parameter flow cytometry and high-dimensional data analysis. This data will then be used to inform ex vivo assays addressing how asthma modifies the function of human DCs and Tregs, and direct mechanistic studies in refined murine models of allergic airway inflammation. Our goal is to discover novel immune networks and mechanisms that can be targeted for future development of innovative, tailored, human asthma therapies. More broadly, this collaborative project with GSK will provide novel insight into disease mechanisms to better tailor existing treatments, and support the development of new therapeutics, for inflammatory diseases of the lung, intestine and other tissues.