1. Immunology and Inflammation
Download icon

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
Research Article
  • Cited 3
  • Views 1,142
  • Annotations
Cite this article as: eLife 2017;6:e32497 doi: 10.7554/eLife.32497

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.

Data availability

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.

Metrics

  • 1,142
    Page views
  • 189
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

    1. Epidemiology and Global Health
    2. Immunology and Inflammation

    A recombinant protein containing influenza viral conserved epitopes and superantigen induces broad-spectrum protection

    Yansheng Li et al.
    Research Article Updated

    Influenza pandemics pose public health threats annually for lacking vaccine that provides cross-protection against novel and emerging influenza viruses. Combining conserved antigens that induce cross-protective antibody responses with epitopes that activate cross-protective T cell responses might be an attractive strategy for developing a universal vaccine. In this study, we constructed a recombinant protein named NMHC that consists of influenza viral conserved epitopes and a superantigen fragment. NMHC promoted the maturation of bone marrow-derived dendritic cells and induced CD4+ T cells to differentiate into Th1, Th2, and Th17 subtypes. Mice vaccinated with NMHC produced high levels of immunoglobulins that cross-bound to HA fragments from six influenza virus subtypes with high antibody titers. Anti-NMHC serum showed potent hemagglutinin inhibition effects to highly divergent group 1 (H1 subtype) and group 2 (H3 subtype) influenza virus strains. Furthermore, purified anti-NMHC antibodies bound to multiple HAs with high affinities. NMHC vaccination effectively protected mice from infection and lung damage when exposed to two subtypes of H1N1 influenza virus. Moreover, NMHC vaccination elicited CD4+ and CD8+ T cell responses that cleared the virus from infected tissues and prevented virus spread. In conclusion, this study provides proof of concept that NMHC vaccination triggers B and T cell immune responses against multiple influenza virus infections. Therefore, NMHC might be a candidate universal broad-spectrum vaccine for the prevention and treatment of multiple influenza viruses.

    1. Immunology and Inflammation

    The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice

    Rafael Bayarri-Olmos et al.
    Research Article Updated

    The alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a fitness advantage that could be driven by the receptor-binding domain (RBD) residue change (N501Y), which also emerged independently in other variants of concern such as the beta/B.1.351 and gamma/P.1 strains. Here, we present a functional characterization of the alpha/B.1.1.7 variant and show an eightfold affinity increase towards human angiotensin-converting enzyme-2 (ACE-2). In accordance with this, transgenic hACE2 mice showed a faster disease progression and severity after infection with a low dose of B.1.1.7, compared to an early 2020 SARS-CoV-2 isolate. When challenged with sera from convalescent individuals or anti-RBD monoclonal antibodies, the N501Y variant showed a minor, but significant elevated evasion potential of ACE-2/RBD antibody neutralization. The data suggest that the single asparagine to tyrosine substitution remarkable rise in affinity may be responsible for the higher transmission rate and severity of the B.1.1.7 variant.

    1. Computational and Systems Biology
    2. Immunology and Inflammation

    TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs

    Koshlan Mayer-Blackwell et al.
    Research Article

    T-cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages experimentally inferred antigen-associated TCRs to form meta-clonotypes – groups of biochemically similar TCRs – that can be used to robustly quantify functionally similar TCRs in bulk repertoires across individuals. We apply the framework to TCR data from COVID-19 patients, generating 1831 public TCR meta-clonotypes from the SARS-CoV-2 antigen-associated TCRs that have strong evidence of restriction to patients with a specific human leukocyte antigen (HLA) genotype. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 59.7% (1093/1831) were more abundant among COVID-19 patients that expressed the putative restricting HLA allele (false discovery rate [FDR]<0.01), demonstrating the potential utility of meta-clonotypes as antigen-specific features for biomarker development. To enable further applications, we developed an open-source software package, tcrdist3, that implements this framework and facilitates flexible workflows for distance-based TCR repertoire analysis.