Discovery and characteristics of trained immunity
Freudenberg et al. 12 reported that in mice, macrophages primarily stimulated by sepsis or high-dose lipopolysaccharide (LPS) induce immune tolerance and exhibit a suppressed immune response to avoid the development of a state of excessive inflammation on secondary challenge. Quintin et al.13 also showed that whereas macrophages can be trained by β-glucan (the main cell wall structural component of the yeastCandida albicans ), mice lacking functional T and B lymphocytes are protected against reinfection of multiple pathogens such as C. albicans and Staphylococcus aureus . Indeed, increasing number of studies have indicated that bacterial, fungal, parasitic, and viral infections can train monocytes/macrophages to promote the secretion of inflammatory cytokines and enhance phagocytosis in response to secondary stimulation, thereby confirming the universality of macrophage memory13-17. In addition to studies using animal models, a study on childhood vaccination reported that the Bacillus Calmette-Guérin (BCG) vaccination can enhance the defense against infections other than those caused by mycobacteria in a monocyte-dependent manner, thereby leading to an overall reduction in child mortality 18. Furthermore, accumulating epidemiological data indicates that live vaccines, such as the measles, smallpox, and polio vaccines, provide non-specific protective effects against a broad range of infections other than those caused by the respective target viruses 19-22.
These studies have revealed two important characteristics of trained immunity. Firstly, trained immunity is a non-specific or semi-specific phenomenon, with its specificity being lower than that of adaptive immunity; and as such, it can provide cross-protection against a wide range of pathogens. Secondly, trained immunity primarily stimulated by infections or vaccines induces a pro-inflammatory or anti-inflammatory secondary immune response independent of classical T/B cell adaptive immunity.