Discovering new pathways of lymphocyte specification and function

The co-ordinated development and differentiation of lymphocytes is critical to producing the bespoke immune responses required to combat specific pathogens, but also to maintaining tissue homeostasis and repair. However, dysregulated immune reactions underlie undesirable chronic inflammation and autoimmunity. Our discovery of type-2 innate lymphoid cells (ILC2) and the description of other ILC subsets has highlighted additional, previously unappreciated, complexity in the processes of lymphocyte specialisation. Our challenge is to unravel the microenvironmental cues, critical cell-surface receptors, and key transcription factor interactions that lead to lymphocyte specification, tissue-specific roles and cellular interactions. We will employ a unique repertoire of lymphocyte transcription factor reporter “polychromILC” mice in combination with CRISPR-mediated screens to identify new regulators of lymphocyte development, differentiation and function. To facilitate the investigation of these new pathways in specific lymphocyte subsets in vivo we will produce a new generation of mouse strains designed to limit off-target events by employing multiple positive and negative determinants, comparable to Boolean operators (AND, OR, NOT or AND NOT). Finally, using a combination of genetic screens and in toto adaptive light-sheet microscopy we aim to define molecules and cells that delineate the migration and development of ILC in the context of the stromal environment.