Designing human ILC fate, function and fitness – ILC_BY_DESIGN

Immune responses against pathogens occur in waves that include ‘innate’ (early) and ‘adaptive’ (delayed) phases. Schematically, myeloid cells act as sentinels and are the first to be activated while antigen-specific B and T lymphocytes providing long-lasting immune memory emerge weeks later. Different types of helper T cells (Th) orchestrate adaptive immune responses by producing soluble factors (cytokines) that are essential in pathogen- and anti-tumor immune responses. Interestingly, it has been recently shown that cytokine production from a family of ‘innate lymphoid cells’ (ILCs) also contribute to the early immune responses during infections, inflammation, stress and tissue repair in both mice and humans. Indeed, three groups of ILCs (ILC1, ILC2, ILC3) are currently considered to be innate homologues of T helper (Th)1, Th2 and Th17/22 T cell subsets, respectively, due to striking similarities in their transcription factor (TF) expression signatures (TBET, GATA3, RORC) and cytokine production (IFN-g, IL-5/IL-13, IL-17A/IL-22) profiles. However, while we have accumulated valuable knowledge on the process that regulate Th differentiation, how mature ILC arise from recently described ILC precursors (ILCP) remains largely unknown. Here, we hypothesize that the rules of Th differentiation also guide human ILC maturation. In this project, we intend to decipher the mechanisms underlying human ILC fate, function and fitness using a robust in vitro culture model and state of the art genetic approaches. The fundamental knowledge obtained will have important implications for our understanding of how immune responses are determined and how protective immunity may be assured. Ultimately, this project should allow for the generation of novel custom-designed human ILCs having defined stable properties, unique specificities and potent clinical applications.