Partially Maintaining E Protein Activity During ILC Development Selectively Inhibits ILC2 Development

Abstract

Abstract Innate lymphoid cells (ILCs) provide an early response to pathogenic damage at mucosal barrier surfaces. They have beneficial roles in infection and tissue repair, as well as pathogenic roles in chronic inflammatory diseases. ILC effector subsets are defined by transcription factor expression patterns and cytokine production profiles. Recent evidence suggests ILC cytokine profiles are not static and cells can be pushed into producing different cytokines. The possibility of manipulating ILCs toward beneficial immune responses or away from pathogenic responses increases the urgency to understand how ILC effector programs are established during ILC development and maintained during homeostasis and immune responses. All ILCs are generated from a common precursor derived from the common lymphoid progenitor, and differentiation of this precursor into ILC1s, ILC2s, and ILC3s is characterized by induction of distinct transcription factors. All ILC subsets share a developmental requirement for Id2 induction. Id2 is an inhibitor of E protein transcription factor activity, but its specific functions in ILC development have not been elucidated. We have used expression of ET-2, a chimeric protein that acts as an Id dominant negative inhibitor, to partially block Id2 function during ILC development. Our experiments show that while ILC1s and ILC3s are mostly undisturbed by ET-2, ILC2s experience a profound block in development. These results demonstrate that, while all ILCs require Id2 expression, ILC2s are uniquely sensitive to the effects of ET-2 and require a more complete inhibition of E protein activity.