During development, haematopoietic stem and progenitor cells (HSPCs) experiencing high cellular stress produce increased levels of calreticulin, which triggers their engulfment by macrophages. A study now shows that repetitive elements promote the expression of β2-microglobulin (B2M) in HSPCs to prevent their engulfment by macrophages.

Pessoa Rodrigues et al. performed a genome-wide screen in human cells and found that Toll-like receptor 3 (TLR3) regulated the expression of a ‘don’t eat-me’ signal, namely B2M. The authors then used zebrafish as a model and showed that depletion of tlr3 reduced the number of B2m+ HSPCs and enhanced HSPC engulfment by macrophages. B2m on HSPCs protected them from phagocytosis in the embryo and impacted HSPC clonality in adults. A series of analyses and functional experiments ultimately suggested a model in which endogenous repetitive elements in HSPCs trigger TLR3 signalling, which promotes the expression of B2M; then, in turn, B2M on the HSPC surface prevents HSPC phagocytosis by macrophages. Finally, the researchers presented evidence of potential conservation in mammals.