The transcriptional repressor HIC1 is required for the maintenance of tissue-resident ILC1

Abstract The group 1 innate lymphoid cell compartment is comprised of conventional natural killer (cNK) and type 1 innate lymphoid cells (ILC1). Within the innate lymphoid cell pool, these cells are delineated by expression of the transcription factor TBET, and both subtypes express cell surface receptors NK1.1 and NKp46. Functionally, ILC1 and cNK cells have been shown to mediate pathogen clearance and tumour control through release of type 1 cytokines, particularly IFN-□. While being closely related, a key feature distinguishing ILC1 from cNK cells is their propensity to reside within a tissue niche rather than enter the circulation. However, the precise mechanisms that regulate tissue residency of ILC1s remain unknown. Here, we show that the transcription factor Hypermethylated in Cancer 1 (HIC1) is a critical control point in the development and maintenance of ILC1. In the liver, HIC1 expression is restricted to the ILC1 compartment. Deletion of HIC1 in NKp46 +cells (Hic1 ΔNcr1mice) resulted in a specific and significant reduction in liver-resident ILC1, while cNK cells were unaffected. Additionally, we show that cNK cells isolated from Hic1 ΔNcr1mice are incapable of restoring the ILC1 compartment in lymphocyte-deficient hosts, unlike wild type donors. Thus, our results identify an important role for HIC1 in the development and maintenance of peripheral ILC1.