Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development

Abstract

The binding of angiopoietin-like proteins to immune-inhibitory receptors maintains ‘stemness’ of haematopoietic stem cells and supports leukaemia development. Cheng Cheng Zhang and colleagues have identified human immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue, paired immunoglobulin-like receptor (PIRB), as the receptors for several angiopoietin-like proteins (ANGPTLs) that are considered 'orphan ligands'. Binding of ANGPTLs to the receptor maintains the 'stemness' of haematopoietic stem cells. LILRB2 and PIRB are regarded as classical immune-inhibitory receptors, and are expressed on leukaemic stem cells as well as on haematopoietic stem cells, revealing an unexpected potential link between the immune system and the maintenance of stemness in normal adult stem cells and in cancer development. How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo1,2,3,4,5,6,7,8,9,10. ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered ‘orphan ligands’ because no receptors were identified3,11,12. Here we show that the immune-inhibitory receptor human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue paired immunoglobulin-like receptor (PIRB) are receptors for several ANGPTLs. LILRB2 and PIRB are expressed on human and mouse HSCs, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of HSCs. In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development. Our study indicates an unexpected functional significance of classical immune-inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development.