Center for Cancer and Immunology Research, Children's Research Institute, Children’s National Medical Center, Washington, United States; Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
Peiying Ye
Center for Cancer and Immunology Research, Children's Research Institute, Children’s National Medical Center, Washington, United States
Christopher A Lazarski
Center for Cancer and Immunology Research, Children's Research Institute, Children’s National Medical Center, Washington, United States
Qi Wu
Department of Neurology, University of Michigan Medical School, Ann Arbor, United States
Ingrid L Bergin
ULAM In-Vivo Animal Core, University of Michigan Medical School, Ann Arbor, United States
Timothy P Bender
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, United States
Michael N Hall
Biozentrum, University of Basel, Basel, Switzerland
Ya Cui
Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
Liguo Zhang
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
Taijiao Jiang
Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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.
