Fig. 2 |. Central and peripheral trained immunity.

Although trained immunity was first established in cells of the mononuclear phagocyte lineage (that is, monocytes and macrophages), monocytes have a relatively short lifespan and are unlikely to transmit their memory phenotype to their progeny and provide sustainable protection. Thus, current vaccine strategies that directly target monocytes or macrophages may have limited capacity for generating sustained innate immune memory. By contrast, haematopoietic stem cells (HSCs) are long-lived cells with self-renewal properties that reside in the bone marrow. The bone marrow is the site of haematopoiesis where HSCs continually undergo asymmetric division giving rise to the full repertoire of myeloid and lymphoid cell types. HSCs can directly respond to acute and chronic infections. Although the exact mechanisms of precursor proliferation or differentiation are not well understood, persistent activation of HSCs can result in their exhaustion, leading to devastating effects on the systemic immune compartment. Monocytes derived from trained HSCs migrate to peripheral organs, where they give rise to monocyte-derived macrophages with enhanced effector functions against different types of pathogens. Natural killer (NK) cells possess adaptive immune characteristics following infection. On reinfection, these memory NK cells undergo a secondary expansion and can more rapidly degranulate and release cytokines, resulting in a more protective immune response. Epithelial stem cells show memory functions during human allergic inflammatory disease, displaying changes in the chromatin accessibility when the stimulus is withdrawn. BCG, bacillus Calmette–Guérin; CMP, common myeloid progenitor: GMP, granulocyte–macrophage progenitor ; MPP, multipotent progenitor.