Discovering the Diversity and its Drivers of Novel Lung Dendritic Cell Subsets in Asthma

Dendritic cells are critical immune sentinel cells that initiate and drive specific immune responses. While they are important for induction of protective adaptive immunity against pathogens, they also play a key role in mediating aberrant inflammation including in allergic disease. Indeed, due to their ability to promote tolerance to innocuous antigens, they are key players in shaping if and how the organism will respond to allergens and thus play an essential role in allergic diseases such as Asthma. Dendritic cells consist of a heterogeneous group of cell subsets, whose distinct and overlapping functions still remain not fully understood. Furthermore, how this diversity of dendritic cells is impacted by Asthma and how this in turn may drive detrimental lung inflammation remains unknown. In this project, we aim to determine the identity, tissue localization, transcriptional regulators and function of lung DCs, with a focus on their role in Asthma. Deep transcriptomic profiling of lung DC subsets will allow establishment of clear subset identities. This will then be leveraged with advanced bioinformatic analysis approaches to identify and validate novel lineage-defining transcription factors of lung DC subsets, focusing on less well characterized sub-populations. Furthermore, we will use it to generate novel transgenic mice with Cre recombinase expression specifically in key DC subsets of interest. These new tools will then be used to elucidate the specific localization patterns of lung DCs as well as the function of these enigmatic cells in vitro and in vivo in the context of asthma. Taken together, this project will provide fundamental insights into the diversity of lung DCs, their key regulators and how they impact allergic lung disease, potentially laying the groundwork for many future studies in this field.