A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1 in mice

  1. Fei Tang
  2. Peng Zhang
  3. Peiying Ye
  4. Christopher A Lazarski
  5. Qi Wu
  6. Ingrid L Bergin
  7. Timothy P Bender
  8. Michael N Hall
  9. Ya Cui
  10. Liguo Zhang
  11. Taijiao Jiang
  12. Yang Liu  Is a corresponding author
  13. Pan Zheng  Is a corresponding author
  1. Children's National Medical Center, United States
  2. University of Michigan Medical School, United States
  3. University of Virginia, United States
  4. University of Basel, Switzerland
  5. Institute of Biophysics, Chinese Academy of Sciences, China

Abstract

Adaptive autoimmunity is restrained by controlling population sizes and pathogenicity of harmful clones, while innate destruction is controlled at effector phase. We report here that deletion of Rptor in mouse hematopoietic stem/progenitor cells causes self-destructive innate immunity by massively increasing the population of previously uncharacterized innate myelolymphoblastoid effector cells (IMLECs). Mouse IMLECs are CD3-B220-NK1.1-Ter119- CD11clow/-CD115-F4/80low/-Gr-1- CD11b+, but surprisingly express high levels of PD-L1. Although they morphologically resemble lymphocytes and actively produce transcripts from Immunoglobulin loci, IMLECs have non-rearranged Ig loci, are phenotypically distinguishable from all known lymphocytes, and have a gene signature that bridges lymphoid and myeloid leukocytes. Rptor deletion unleashes differentiation of IMLECs from common myeloid progenitor cells by reducing expression of Myb. Importantly, IMLECs broadly overexpress pattern-recognition receptors and their expansion causes systemic inflammation in response to Toll-like receptor ligands in mice. Our data unveil a novel leukocyte population and an unrecognized role of Raptor/mTORC1 in innate immune tolerance.

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The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Fei Tang

    Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Peng Zhang

    Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6218-1885
  3. Peiying Ye

    Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Christopher A Lazarski

    Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Qi Wu

    Department of Neurology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ingrid L Bergin

    ULAM Pathology Cores for Animal Research, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Timothy P Bender

    Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Michael N Hall

    Biozentrum, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  9. Ya Cui

    Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Liguo Zhang

    Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Taijiao Jiang

    Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Yang Liu

    Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
    For correspondence
    yaliu@cnmc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9442-700X
  13. Pan Zheng

    Center for Cancer and Immunology Research, Children's National Medical Center, Washington, United States
    For correspondence
    pzheng@cnmc.org
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institute of Allergy and Infectious Diseases (AI64350)

  • Yang Liu
  • Pan Zheng

National Cancer Institute (CA183030)

  • Yang Liu

National Institute on Aging (AG036690)

  • Pan Zheng

National Cancer Institute (CA171972)

  • Yang Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal careand use committee (IACUC) protocols (312-13-12 and #00030574) of the Children's National Medical Center. Every effort was made to minimize suffering.

Reviewing Editor

  1. Satyajit Rath, Agharkar Research Institute (ARI) and Indian Institute of Science Education and Research (IISER), India

Publication history

  1. Received: October 3, 2017
  2. Accepted: December 2, 2017
  3. Accepted Manuscript published: December 5, 2017 (version 1)
  4. Version of Record published: January 10, 2018 (version 2)

Copyright

© 2017, Tang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Fei Tang
  2. Peng Zhang
  3. Peiying Ye
  4. Christopher A Lazarski
  5. Qi Wu
  6. Ingrid L Bergin
  7. Timothy P Bender
  8. Michael N Hall
  9. Ya Cui
  10. Liguo Zhang
  11. Taijiao Jiang
  12. Yang Liu
  13. Pan Zheng
(2017)
A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1 in mice
eLife 6:e32497.
https://doi.org/10.7554/eLife.32497
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