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

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 <i>Rptor</i> 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 <i>Ig</i> loci, are phenotypically distinguishable from all known lymphocytes, and have a gene signature that bridges lymphoid and myeloid leukocytes. <i>Rptor</i> deletion unleashes differentiation of IMLECs from common myeloid progenitor cells by reducing expression of <i>Myb</i>. 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.