Hematopoietic stem and progenitor cells confer cross-protective trained immunity in mouse models

Recent studies suggest that infection reprograms hematopoietic stem and progenitor cells (HSPCs) to enhance innate immune responses upon secondary infectious challenge, a process called trained immunity.However, the specificity and cell types responsible for this response remain poorly defined. We established a model of trained immunity in mice in response to Mycobacterium avium infection. scRNA-seq analysis revealed that HSPCs activate interferon gamma-response genes heterogeneously upon primary challenge, while rare cell populations expand. Macrophages derived from trained HSPCs demonstrated enhanced bacterial killing and metabolism, and a single dose of recombinant interferon gamma exposure was sufficient to induce similar training. Mice transplanted with influenza -trained HSPCs displayed enhanced immunity against M. avium challenge and vice versa, demonstrating cross protection against antigenically distinct pathogens. Together, these results indicate that heterogeneous responses to infection by HSPCs can lead to long-term production of bone marrow derived macrophages with enhanced function and confer cross-protection against alternative pathogens.

Automated summary

Recent studies have found that infection can reprogram hematopoietic stem and progenitor cells (HSPCs) to enhance innate immune responses, a phenomenon known as trained immunity. In this study using mice, it was discovered that HSPCs activate interferon gamma-response genes heterogeneously upon primary infection, and rare cell populations expand. Macrophages derived from trained HSPCs demonstrated enhanced bacterial killing and metabolism, and a single dose of recombinant interferon gamma exposure was enough to induce similar training. Furthermore, transplantation of influenza-trained HSPCs in mice resulted in enhanced immunity against M. avium, demonstrating cross-protection against different pathogens. These findings suggest that HSPCs can produce long-term bone marrow derived macrophages with enhanced function and provide cross-protection against alternative pathogens.