Identification of aceNKPs, a committed common progenitor population of the ILC1 and NK cell continuum

Rodriguez-Rodriguez, Noe and Clark, Paula A. and Gogoi, Mayuri and Ferreira, Ana C. F. and Kerscher, Bernhard and Crisp, Alastair and Jolin, Helen E. and Murphy, Jane E. and Sivasubramaniam, Meera and Pedro, Luisa and Walker, Jennifer A. and Heycock, Morgan W. D. and Shields, Jacqueline D. and Barlow, Jillian L. and McKenzie, Andrew N. J. (2022) Identification of aceNKPs, a committed common progenitor population of the ILC1 and NK cell continuum. Proceedings of the National Academy of Sciences of the United States of America, 119 (49). e2203454119. ISSN 0027-8424 (https://doi.org/10.1073/pnas.2203454119)

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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.

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