The ageing immune system is characterized by weaker adaptive immune responses and increased inflammatory pathology. Here, Ross et al. show that antibody-mediated depletion of myeloid-biased haematopoietic stem cells (HSCs) can protect against such age-associated dysfunction.

HSCs can be broadly divided into two subsets: balanced HSCs, which lead to equal production of lymphoid and myeloid cells; and myeloid HSCs, which mainly give rise to myeloid cells. The ratio of myeloid to balanced HSCs increases with age, and this is thought to contribute to immune dysfunction. The authors set out to define surface antigens that can be used to target myeloid HSCs. By screening transcriptional datasets of HSCs, they found 12 candidate genes, with antibody-staining analyses identifying CD150, CD41, CD62p and NEO1 as candidate antigens for selectively targeting myeloid HSCs.

Using these markers and other refinements, the authors optimized an antibody-based protocol for depleting myeloid HSCs. Adult mice depleted of myeloid HSCs showed an increase in common lymphoid progenitors (CLPs) and a decrease in myeloid progenitors. Depletion of myeloid HSCs increased the naive T cell and mature B cell compartments in aged mice and reduced the frequencies of CD4+ T cells with an ‘exhausted’ phenotype. Aged mice depleted of myeloid HSCs also had reduced frequencies of age-associated B cells and lower levels of circulating pro-inflammatory mediators. Moreover, depletion of HSCs in aged mice improved their immune responses during vaccination and subsequent challenge with a pathogenic virus.

Importantly, the antigens used to define myeloid HSCs in mice also marked a subset of HSCs in humans, and these antigens were enriched in HSCs from patients with diseases associated with ageing of the immune system. As such, these findings could pave the way for therapies that rejuvenate the ageing immune system in humans.