The cells that mediate innate immune memory and their functional significance in inflammatory and infectious diseases

- Monocytes/macrophages can be trained to be more responsive to secondary stimuli.
- NK cells have properties of classical adaptive memory and trained innate immunity.
- Trained innate immunity can confer non-specific protection against infection.
- Training innate immune regulation or unresponsiveness can control inflammation.

Immunological memory mediated by antigen-specific T and B cells is the foundation of adaptive immunity and is fundamental to the heightened and rapid protective immune response induced by vaccination or following re-infection with the same pathogen. While the innate immune system has classically been considered to be non-specific and devoid of memory, it now appears that it can be trained following exposure to microbes or their products and that this may confer a form of memory on innate immune cells. The evidence for immunological memory outside of T and B cells has been best established for natural killer (NK) cells, where it has been known for decades that NK cells have heighten responses following immunological re-challenge. Furthermore, recent studies have demonstrated that monocyte/macrophages, and probably dendritic cells, can be re-programmed through epigenetic modification, following exposure to pathogens or their products, resulting in heighted responses following a second stimulation. Unlike antigen-specific memory of the adaptive immune system, the second stimulation does not have to be with the same pathogen or antigen. Indirect evidence for this comes from reports on the non-specific beneficial effect of certain live vaccines, such as Bacillus Calmette Guerin (BCG) against unrelated childhood infectious diseases. It also appears that certain pathogen or pathogen-derived molecules can prime immune cells, especially macrophages, to secrete more anti-inflammatory and less pro-inflammatory cyokines, thus opening up the possibility of exploiting innate immune training as a new therapeutic approach for inflammatory diseases.