Delta-like 4-Derived Notch Signals Differentially Regulate Thymic Generation of Skin-Homing CCR10+NK1.1+ Innate Lymphoid Cells at Neonatal and Adult Stages

Abstract

The thymus is a primary lymphoid organ for T cell development. Increasing evidence found that the thymus is also an important site for development of innate lymphoid cells (ILCs). ILCs generated in thymi acquire unique homing properties that direct their localization into barrier tissues such as the skin and intestine, where they help local homeostasis. Mechanisms underlying the developmental programming of unique tissue-homing properties of ILCs are poorly understood. We report in this article that thymic stroma-derived Notch signaling is differentially involved in thymic generation of a population of NK1.1⁺ group 1 ILCs (ILC1s) with the CCR10⁺ skin-homing property in adult and neonatal mice. We found that thymic generation of CCR10⁺NK1.1⁺ ILC1s is increased in T cell-deficient mice at adult, but not neonatal, stages, supporting the notion that a large number of developing T cells interfere with signals required for generation of CCR10⁺NK1.1⁺ ILC1s. In an in vitro differentiation assay, increasing Notch signals promotes generation of CCR10⁺NK1.1⁺ ILC1s from hematopoietic progenitors. Knockout of the Notch ligand Delta-like 4 in thymic stroma impairs generation of CCR10⁺NK1.1⁺ ILC1s in adult thymi, but development of CCR10⁺NK1.1⁺ ILC1s in neonatal thymi is less dependent on Delta-like 4-derived Notch signals. Mechanistically, the Notch signaling is required for proper expression of the IL-7R CD127 on thymic NK1.1⁺ ILC1s, and deficiency of CD127 also impairs thymic generation of CCR10⁺NK1.1⁺ ILC1s at adult, but not perinatal, stages. Our findings advanced understanding of regulatory mechanisms of thymic innate lymphocyte development.