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

Fei Tang; Peng Zhang; Peiying Ye; Christopher A Lazarski; Qi Wu; Ingrid L Bergin; Timothy P Bender; Michael N Hall; Ya Cui; Liguo Zhang; Taijiao Jiang; Yang Liu; Pan Zheng

doi:10.7554/eLife.32497

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

Elife. 2017 Dec 5:6:e32497. doi: 10.7554/eLife.32497.

Authors

Fei Tang¹, Peng Zhang^{1

2}, Peiying Ye¹, Christopher A Lazarski¹, Qi Wu³, Ingrid L Bergin⁴, Timothy P Bender⁵, Michael N Hall⁶, Ya Cui², Liguo Zhang⁷, Taijiao Jiang², Yang Liu¹, Pan Zheng¹

Affiliations

¹ Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, United States.
² Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
³ Department of Neurology, University of Michigan Medical School, Ann Arbor, United States.
⁴ ULAM In-Vivo Animal Core, University of Michigan Medical School, Ann Arbor, United States.
⁵ Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, United States.
⁶ Biozentrum, University of Basel, Basel, Switzerland.
⁷ Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 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^- 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.

Keywords: TSC-mTOR signaling; hemotopoiesis; immune tolerance; immunology; inflammation; innate immunity; mTORC1; mouse.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antigens, Surface / analysis
Autoimmunity*
Cell Proliferation*
Gene Deletion
Immunity, Innate*
Immunophenotyping
Lymphocyte Subsets / physiology*
Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
Mice
Regulatory-Associated Protein of mTOR / genetics

Substances

Antigens, Surface
Regulatory-Associated Protein of mTOR
Rptor protein, mouse
Mechanistic Target of Rapamycin Complex 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding