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

Noe Rodriguez-Rodriguez; Paula A. Clark; Mayuri Gogoi; Ana C. F. Ferreira; Bernhard Kerscher; Alastair Crisp; Helen E. Jolin; Jane E. Murphy; Meera Sivasubramaniam; Luisa Pedro; Jennifer A. Walker; Morgan W. D. Heycock; Jacqueline D. Shields; Jillian L. Barlow; Andrew N. J. McKenzie

doi:10.1073/pnas.2203454119

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

Noe Rodriguez-Rodriguez^*, Paula A. Clark, Mayuri Gogoi, Ana C. F. Ferreira, Bernhard Kerscher, Alastair Crisp, Helen E. Jolin, Jane E. Murphy, Meera Sivasubramaniam, Luisa Pedro, Jennifer A. Walker, Morgan W. D. Heycock, Jacqueline D. Shields, Jillian L. Barlow^*, Andrew N. J. McKenzie^*

^*Corresponding author for this work

Strathclyde Institute Of Pharmacy And Biomedical Sciences

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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.

Original language	English
Article number	e2203454119
Number of pages	12
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	49
DOIs	https://doi.org/10.1073/pnas.2203454119
Publication status	Published - 6 Dec 2022

Funding

This study was supported by grants from the UK Medical Research Council (U105178805) and Wellcome Trust (100963/Z/13/Z and 220223/Z/20/Z). N.R.-R. has grant funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement number 896454. J.E.M. was supported by the Rosetrees Trust.

Keywords

hematopoiesis
ILC1s
innate lymphoid cells
NK cells
NKG2A/C/E

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Rodriguez-Rodriguez, N., Clark, P. A., Gogoi, M., Ferreira, A. C. F., Kerscher, B., Crisp, A., Jolin, H. E., Murphy, J. E., Sivasubramaniam, M., Pedro, L., Walker, J. A., Heycock, M. W. D., Shields, J. D., Barlow, J. L., & McKenzie, A. 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), Article e2203454119. https://doi.org/10.1073/pnas.2203454119

@article{39c78e778edf4b179ec6011a949f1989,

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

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.",

keywords = "hematopoiesis, ILC1s, innate lymphoid cells, NK cells, NKG2A/C/E",

author = "Noe Rodriguez-Rodriguez and Clark, {Paula A.} and Mayuri Gogoi and Ferreira, {Ana C. F.} and Bernhard Kerscher and Alastair Crisp and Jolin, {Helen E.} and Murphy, {Jane E.} and Meera Sivasubramaniam and Luisa Pedro and Walker, {Jennifer A.} and Heycock, {Morgan W. D.} and Shields, {Jacqueline D.} and Barlow, {Jillian L.} and McKenzie, {Andrew N. J.}",

year = "2022",

month = dec,

day = "6",

doi = "10.1073/pnas.2203454119",

language = "English",

volume = "119",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

number = "49",

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Rodriguez-Rodriguez, N, Clark, PA, Gogoi, M, Ferreira, ACF, Kerscher, B, Crisp, A, Jolin, HE, Murphy, JE, Sivasubramaniam, M, Pedro, L, Walker, JA, Heycock, MWD, Shields, JD, Barlow, JL & McKenzie, ANJ 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, vol. 119, no. 49, e2203454119. https://doi.org/10.1073/pnas.2203454119

TY - JOUR

T1 - Identification of aceNKPs, a committed common progenitor population of the ILC1 and NK cell continuum

AU - Rodriguez-Rodriguez, Noe

AU - Clark, Paula A.

AU - Gogoi, Mayuri

AU - Ferreira, Ana C. F.

AU - Kerscher, Bernhard

AU - Crisp, Alastair

AU - Jolin, Helen E.

AU - Murphy, Jane E.

AU - Sivasubramaniam, Meera

AU - Pedro, Luisa

AU - Walker, Jennifer A.

AU - Heycock, Morgan W. D.

AU - Shields, Jacqueline D.

AU - Barlow, Jillian L.

AU - McKenzie, Andrew N. J.

PY - 2022/12/6

Y1 - 2022/12/6

N2 - 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.

AB - 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.

KW - hematopoiesis

KW - ILC1s

KW - innate lymphoid cells

KW - NK cells

KW - NKG2A/C/E

U2 - 10.1073/pnas.2203454119

DO - 10.1073/pnas.2203454119

M3 - Article

C2 - 36442116

AN - SCOPUS:85142900869

SN - 0027-8424

VL - 119

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 49

M1 - e2203454119

ER -

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

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