Immunomodulation and immune memory in HSC: new functions for new therapeutic applications?

Classically, hematopoietic stem cells (HSC) are only seen as supplier of a sufficient number of mature cells, whereas the regulation of the immune response has been thought to be exclusively mediated by the differentiated effector cells of the immune system. However, we and others have shown that HSCs can directly sense both cytokines released during infection and inflammation, such as M-CSF, and pathogen associated molecular patterns (PAMP). This direct sensing leads to instruction of myeloid differentiation in HSC thus changing dramatically both number and composition of the produced effector cells and contributing to an effective immune response that can be used for therapeutic applications.

Now we show that HSC can directly sense Brucela abortus, a gram-negative coccobacillus, through SLAM/CD150 receptor, nowadays the best marker for identification of the long-term HSC but so far of unknown function in HSC. Using an early myeloid commitment reporter mouse model, we demonstrate that HSC can sense directly the bacteria via a direct interaction of SLAM/CD150 with the bacteria outer membrane protein Omp25. This interaction induces a functional commitment of HSC in the bone marrow toward the myeloid lineage, leading to an increased production of downstream myeloid progenitor and mature cell. This provide the first demonstration of a direct recognition of a live pathogen by HSCs via SLAM/CD150.

In addition, we show that HSC can present an immune memory. HSC drive a more rapid and efficient immune response if they have previously been exposed to LPS. Acute immune stimulation with LPS induced persistent alterations in accessibility of specific myeloid lineage enhancers, as accessed by ATAC-seq on rare HSC, which increases responsiveness of associated immune genes to secondary stimulation. Functionally, this is associated with increased myelopoiesis of pre-exposed HSC and improves innate immunity against the gram-negative bacterium P. aeruginosa. C/EBP is the major actor of memory imprinting, describing a new function for this factor.

Overall, our work demonstrate that HSC are not only at the top of hematopoietic development but also at the heart of the immune response. By sensing directly pathogens and inflammatory cytokines and presenting an innate immune memory, HSC participate much more than originally expected to a global efficient immune response. A better understanding of those newly discovered functions can undoubtedly have significant therapeutic implications.