SUMMARY Trained immunity (TI) has been speculated to serve as a contributor to autoimmune disease (AD) pathogenesis via generation of hyper-inflammatory myeloid cells. Using a mouse model of systemic lupus erythematosus (SLE), we show that hematopoietic stem cells (HSC) constitute a transplantable, long-term reservoir for macrophages that exhibit features of TI, including increased Mycobacterium avium killing, inflammatory cytokine production, and augmented capacity to co-stimulate naive T cells. Strikingly, hematopoietic progenitor cells derived from these HSC exhibit unique molecular features characterized by reduced chromatin accessibility and transcription of metabolic genes, accompanied by reduced glycolysis and central carbon metabolism. Altogether, our data identify HSC as a functional unit of TI in chronic AD, establish increased T-cell costimulatory activity as a potentially pathogenic feature of TI in this setting, and show that macrophages inherit reduced metabolic activity from AD-exposed HSC, suggesting metabolic activation and TI can be decoupled. Our findings thus implicate HSC as a long-term reservoir for TI that could contribute to AD.

Hematopoietic stem cells are a reservoir for trained immunity in autoimmune disease