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Rodriguez-Rodriguez, Noe; Clark, Paula A.; Gogoi, Mayuri; Ferreira, Ana C. F.; Kerscher, Bernhard; Crisp, Alastair; Jolin, Helen E.; Murphy, Jane E.; Sivasubramaniam, Meera; Pedro, Luisa; Walker, Jennifer A.; Heycock, Morgan W. D.; Shields, Jacqueline D.; Barlow, Jillian L. and McKenzie, Andrew N. J.
(2022).
DOI: https://doi.org/10.1073/pnas.2203454119
Abstract
The development of innate lymphoid cell (ILC) transcription factor reporter mice has shown a previously unexpected complexity in ILC hematopoiesis. Using novel polychromic mice to achieve higher phenotypic resolution, we have characterized bone marrow progenitors that are committed to the group 1 ILC lineage. These common ILC1/NK cell progenitors (ILC1/NKP), which we call "aceNKPs", are defined as lineage–Id2+IL-7Rα+CD25–α4β7–NKG2A/C/E+Bcl11b–. In vitro, aceNKPs differentiate into group 1 ILCs, including NK-like cells that express Eomes without the requirement for IL-15, and produce IFN-γ and perforin upon IL-15 stimulation. Following reconstitution of Rag2–/–Il2rg–/– hosts, aceNKPs give rise to a spectrum of mature ILC1/NK cells (regardless of their tissue location) that cannot be clearly segregated into the traditional ILC1 and NK subsets, suggesting that group 1 ILCs constitute a dynamic continuum of ILCs that can develop from a common progenitor. In addition, aceNKP-derived ILC1/NK cells effectively ameliorate tumor burden in a model of lung metastasis, where they acquired a cytotoxic NK cell phenotype. Our results identify the primary ILC1/NK progenitor that lacks ILC2 or ILC3 potential and is strictly committed to ILC1/NK cell production irrespective of tissue homing.