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Title: Fate Decision Between Group 3 Innate Lymphoid and Conventional NK Cell Lineages by Notch Signaling in Human Circulating Hematopoietic Progenitors

Abstract

The role of Notch signaling in human innate lymphoid cell (ILC) differentiation is unclear, although IL-7 and IL-15 promote differentiation of natural cytotoxicity receptor (NCR) NKp44+ group 3 ILCs (NCR+ILC3s) and conventional NK (cNK) cells from CD34 + hematopoietic progenitor cells (HPCs) ex vivo. In this study, we analyzed the functions of Notch in the differentiation of NCR +ILC3s and cNK cells from human HPC subpopulations circulating in peripheral blood by limiting dilution and clonal assays using high-throughput flow cytometry. We demonstrated that Notch signaling in combination with IL-7 induced NCR +ILC3 differentiation, but conversely suppressed IL-15–dependent cNK cell generation in CD45RA+Flt-3-c-Kit low, a novel innate lymphocyte-committed HPC subpopulation. In contrast, Notch signaling induced CD45RA-Flt-3 +c-Kithigh multipotent HPCs to generate CD34 +CD7 +CD62L high, the earliest thymic progenitor–like cells, which preserved high cNK/T cell potential, but lost NCR +ILC3 potential. These findings implicate the countervailing functions of Notch signaling in the fate decision between NCR +ILC3 and cNK cell lineages at different maturational stages of human HPCs. Inhibition of Notch functions by Abs specific for either the Notch1 or Notch2 negative regulatory region suggested that both Notch1 and Notch2 signals were involved in the fate decision of innate lymphocyte-committed HPCsmore » and in the generation of earliest thymic progenitor–like cells from multipotent HPCs. Furthermore, the synergistic interaction between Notch and IL-7 in NCR +ILC3 commitment was primarily explicable by the induction of IL-7 receptor expression in the innate lymphocyte–committed HPCs by Notch stimulation, suggesting the pivotal role of Notch in the transcriptional control required for human NCR +ILC3 commitment.« less

Authors:
 [1];  [1];  [1];  [1]; ORCiD logo [1];  [1];  [2]; ORCiD logo [3];  [1]
  1. Radiation Effects Research Foundation, Hiroshima (Japan). Dept. of Molecular Biosciences
  2. Memorial Sloan- Kettering Cancer Center, New York, NY (United States). Cell Biology Program
  3. Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Dept. of Medicine; Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Immunology Program
Publication Date:
Research Org.:
National Academy of Sciences, Washington, DC (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1546083
Grant/Contract Number:  
HS0000031
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Immunology
Additional Journal Information:
Journal Volume: 199; Journal Issue: 8; Journal ID: ISSN 0022-1767
Publisher:
The American Association of Immunologists, Inc.
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Kyoizumi, Seishi, Kubo, Yoshiko, Kajimura, Junko, Yoshida, Kengo, Hayashi, Tomonori, Nakachi, Kei, Moore, Malcolm A., van den Brink, Marcel R. M., and Kusunoki, Yoichiro. Fate Decision Between Group 3 Innate Lymphoid and Conventional NK Cell Lineages by Notch Signaling in Human Circulating Hematopoietic Progenitors. United States: N. p., 2017. Web. doi:10.4049/jimmunol.1601711.
Kyoizumi, Seishi, Kubo, Yoshiko, Kajimura, Junko, Yoshida, Kengo, Hayashi, Tomonori, Nakachi, Kei, Moore, Malcolm A., van den Brink, Marcel R. M., & Kusunoki, Yoichiro. Fate Decision Between Group 3 Innate Lymphoid and Conventional NK Cell Lineages by Notch Signaling in Human Circulating Hematopoietic Progenitors. United States. doi:10.4049/jimmunol.1601711.
Kyoizumi, Seishi, Kubo, Yoshiko, Kajimura, Junko, Yoshida, Kengo, Hayashi, Tomonori, Nakachi, Kei, Moore, Malcolm A., van den Brink, Marcel R. M., and Kusunoki, Yoichiro. Tue . "Fate Decision Between Group 3 Innate Lymphoid and Conventional NK Cell Lineages by Notch Signaling in Human Circulating Hematopoietic Progenitors". United States. doi:10.4049/jimmunol.1601711. https://www.osti.gov/servlets/purl/1546083.
@article{osti_1546083,
title = {Fate Decision Between Group 3 Innate Lymphoid and Conventional NK Cell Lineages by Notch Signaling in Human Circulating Hematopoietic Progenitors},
author = {Kyoizumi, Seishi and Kubo, Yoshiko and Kajimura, Junko and Yoshida, Kengo and Hayashi, Tomonori and Nakachi, Kei and Moore, Malcolm A. and van den Brink, Marcel R. M. and Kusunoki, Yoichiro},
abstractNote = {The role of Notch signaling in human innate lymphoid cell (ILC) differentiation is unclear, although IL-7 and IL-15 promote differentiation of natural cytotoxicity receptor (NCR) NKp44+ group 3 ILCs (NCR+ILC3s) and conventional NK (cNK) cells from CD34+ hematopoietic progenitor cells (HPCs) ex vivo. In this study, we analyzed the functions of Notch in the differentiation of NCR+ILC3s and cNK cells from human HPC subpopulations circulating in peripheral blood by limiting dilution and clonal assays using high-throughput flow cytometry. We demonstrated that Notch signaling in combination with IL-7 induced NCR+ILC3 differentiation, but conversely suppressed IL-15–dependent cNK cell generation in CD45RA+Flt-3-c-Kitlow, a novel innate lymphocyte-committed HPC subpopulation. In contrast, Notch signaling induced CD45RA-Flt-3+c-Kithigh multipotent HPCs to generate CD34+CD7+CD62Lhigh, the earliest thymic progenitor–like cells, which preserved high cNK/T cell potential, but lost NCR+ILC3 potential. These findings implicate the countervailing functions of Notch signaling in the fate decision between NCR+ILC3 and cNK cell lineages at different maturational stages of human HPCs. Inhibition of Notch functions by Abs specific for either the Notch1 or Notch2 negative regulatory region suggested that both Notch1 and Notch2 signals were involved in the fate decision of innate lymphocyte-committed HPCs and in the generation of earliest thymic progenitor–like cells from multipotent HPCs. Furthermore, the synergistic interaction between Notch and IL-7 in NCR+ILC3 commitment was primarily explicable by the induction of IL-7 receptor expression in the innate lymphocyte–committed HPCs by Notch stimulation, suggesting the pivotal role of Notch in the transcriptional control required for human NCR+ILC3 commitment.},
doi = {10.4049/jimmunol.1601711},
journal = {Journal of Immunology},
number = 8,
volume = 199,
place = {United States},
year = {2017},
month = {10}
}

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