Immunology and Inflammation

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

Children's National Medical Center, United States
University of Michigan Medical School, United States
University of Virginia, United States
University of Basel, Switzerland
Institute of Biophysics, Chinese Academy of Sciences, China

Research Article Dec 5, 2017

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Cite as: eLife 2017;6:e32497 doi: 10.7554/eLife.32497

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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^-CD11c^low/-CD115^-F4/80^low/-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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Author details

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.
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.

0000-0002-6218-1885
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.
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.
Qi Wu

Department of Neurology, University of Michigan Medical School, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
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.
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.
Michael N Hall

Biozentrum, University of Basel, Basel, Switzerland

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The authors declare that no competing interests exist.
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.
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.
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.
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.

0000-0002-9442-700X
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

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

Publication history

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

Copyright

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.