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.
Highlights
Autoreactive T and B lymphocytes are controlled by regulation of population sizes and pathogenicity through clonal deletion (Burnet, 1957), clonal anergy (Nossal and Pike, 1980) and regulatory T cells (Sakaguchi et al, 1995)
We observed the massive accumulation of CD11b+Gr-1- cells in the bone marrow (BM) of RptorF/F, Cre-ER mice after tamoxifen induced targeted mutation of Rptor, which clearly excludes the role of polyinosinic: polycytidylic acid (pIpC) in the generation of these cells (Figure 1—figure supplement 5)
Our data reveal an unexpected function of mTORC1 in suppressing innate myelolymphoblastoid effector cells (IMLECs) expansion
Summary
Autoreactive T and B lymphocytes are controlled by regulation of population sizes and pathogenicity through clonal deletion (Burnet, 1957), clonal anergy (Nossal and Pike, 1980) and regulatory T cells (Sakaguchi et al, 1995). Since innate immune responses triggered by host components can cause fatal tissue damage Immunology eLife digest The cells of the immune system defend us from bacteria, viruses and other microbes that might cause harm to the body. Immune cells develop from stem cells in the bone marrow. The stem cells first develop into one of two types of progenitor cell before specializing further into the different types of mature immune cell. Researchers often categorize immune cells as either myeloid or lymphoid, depending on which progenitor cell they developed from
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