Targeting human Langerhans cells to induce long-lasting tolerance in allergy. (360G-Wellcome-109377_Z_15_Z)

Langerhans cells (LCs) orchestrate cutaneous immune responses, inducing immune activation or tolerance to epicutaneously encountered antigens. Here I hypothesise that identification and targeting of the molecular switches controlling antigen presentation in human LCs will enable the induction of efficient and long lasting tolerance in allergy. Applying the systems immunology approach I developed, I aim to compare whole transcriptomes of LCs isolated from clinical samples from paediatric and adul t patients, exposed or not to an allergen, and ex vivo culture of epidermal sheets subjected to contrasting treatments. Computational analysis of molecular networks, paired with silencing of identified candidate targets, and functional validation of immunological outcomes will allow me to dissect the mechanisms of tolerance induction in human skin. I aim to address the following questions: 1) Is LC ability to induce tolerance impaired in atopic skin? 2) How is the allergen presentation re gulated in human LCs during allergen exposure? 3) How can we target the transcriptional networks in human LCs in order to induce long-lasting allergen tolerance? The outlined investigations will lead to a comprehensive understanding of allergen presentation by human LCs, and to the identification of novel therapeutic targets for induction of long-lasting tolerance in allergy.