A lineage of myelolymphoblastic innate cells unmasked by inactivation of mTOR complex 1

Blockades in hematopoiesis deprive the host of vital blood cells and frequently cause leukemia. Here we show that inactivation of mTORC1 in hematopoietic stem cells by deletion of Raptor unmasked a cell type, hereby called myelolymphoblastic innate cell (MLIC) based on unique gene expression signature, cell surface markers, morphology and functions. The MLICs are CD11b(+)Gr-1(-)B7-H1(high)F4/80(low) and have morphology of lymphoblasts with active Ig loci but no gene rearrangement. Within weeks of Raptor deletion, the MLICs account for nearly 50% of bone marrow cells and are found throughout both the lymphoid and non-lymphoid organs. Nevertheless, the MLICs are not malignant as they undergo very limited proliferation in vivo. Importantly, the MLICs broadly express pattern-recognition receptors and produce large amounts of inflammatory cytokines in response to all TLR ligands tested, rendering the host highly susceptible to pathogen-associated molecular patterns. Our data suggest that hematopoietic cell-intrinsic mTORC1 prevents development of self-destructive innate immune attack by suppressing generation of MLICs. Overall design: Raptor F/F mice were crossed with Mx1-Cre mice for more than 2 generations to get Raptor F/F (Ctrl) and Raptor F/F, Mx1-Cre (cKO) mice. Sex-matched 6-8 weeks old Ctrl mice and cKO mice were treated with polyinosinic: polycytidylic acid (pIpC) every other day for consecutive 7 times by intra-peritoneal (i.p.) injection to induce Cre expression and Raptor deletion in mouse hematopoietic system. Raptor mice were sacrificed 2-3 weeks after the last injection of pIpC. Whole BM cells from Raptor Ctrl mice (n=3) and FACS-sorted CD11b(+)Gr-1(-) BM MLICs from Raptor cKO mice (n=3) were used for RNA isolation and subsequent cDNA libraries construction. mRNA profiles of Ctrl-WBM and cKO-MLIC were examined by RNA-sequencing, in triplicate, using Illumina HiSeq 2000.

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Tang F, Zhang P, Ye P, Lazarski CA, Wu Q, Bergin IL, Bender TP, Hall MN, Cui Y, Zhang L, Jiang T, Liu Y, Zheng P