Trained immunity

"Trained immunity" (TI) or "innate immune memory" is a term for a new immunological concept that describes the adaptive properties of innate immune cells such as macrophages and NK cells. Innate immune cells such as monocytes/macrophages and NK cells are activated by the recognition of PAMPs such as lipopolysaccharides, bacterial DNA and mannans that bind to Toll-like receptors (TLRs) and Nod-like receptors (NLRs). Priming induces a strong protective inflammatory response through the release of cytokines such as IFN-gamma, which provides protection against secondary presentation of PAMPs by the same or a different pathogen than the one that triggered the priming of trained immunity (cross-protection). Epigenetic changes and immune metabolism are the mechanisms underlying the training of immune cells to act efficiently upon a second infection (Netea et al. 2015).

The mechanisms underlying innate immune memory have been extensively studied in recent decades, but still require further elucidation. Although the specificity of adaptive immune memory in vertebrates is ensured by recombination of immunoglobulin family genes and clonal expansion, the basic mechanisms of non-specific enhanced responsiveness of innate immune cells (see below innate immunity) are based on epigenetic, transcriptional and metabolic programs following transient stimulation. Changes in these immunological processes lead to an increased responsiveness to secondary challenges from a variety of stimuli. This phenomenon is referred to as "trained immunity".

On the one hand, trained immunity improves the response to infections and vaccinations by enabling a stronger innate immune response and improved protection against a variety of microbial stimuli. On the other hand, trained immunity may contribute to the pathophysiology of cardiovascular, autoinflammatory and neurodegenerative diseases.

Trained immunity (TI) was first discovered in cells of the innate immune system, e.g. in monocytes, macrophages and natural killer cells. Tissue resident memorycells (TRMs) also provide local protection against infections (and tumors) as tissue-resident CD4+ memory T cells. TRMs develop as specialized memory cells through infections and are therefore part of the TI.

However, trained immunity has also been found in cells that are not part of the innate immune system. These include cells with a long lifespan, such as epithelial stem cells (EpSCs) and fibroblasts (Naik S et al. 2017). It has been shown that epithelial stem cells can develop a long-lasting memory for previous inflammatory stimuli, e.g. topical imiquimod treatment. This enables the skin to react quickly to subsequent damaging stimuli. After the initial stimulus, EpSCs retain chromosomal accessibility of several critical genes for the inflammatory response, enabling rapid transcription of AIM2 and its downstream effector genes upon a secondary stimulus, i.e. skin damage (Naik, S et al. 2017). This memory is mediated by the Aim2 gene encoding an activator of the inflammasome. The absence of the AIM2 protein or its downstream effectors, caspase-1 and interleukin-1beta, abolishes the memory of EpSCs for inflammation (Naik S et al. 2017).

Epigenetic changes and immune metabolism are the mechanisms underlying the training of immune cells to respond efficiently to a second infection (Netea et al. 2015). Recently, Cheng et al. have revealed a new mechanism to support "trained immunity", focusing in particular on cell metabolism such as glycolysis. For example, they showed that the cholesterol synthesis pathway was strongly induced in beta-glucan-trained macrophages (Cheng et al., 2014). The interplay between metabolite production and trained immunity was recently shown (Arts et al. 2016). The cholesterol synthesis pathway requires an intermediate metabolite(mevalonate) that induces a trained immunity profile by promoting the expression of a number of genes required for the beta-glucan-trained immunity phenotype (Arts et al. 2016a; Bekkering et al. 2018). Trained immunity induces aerobic glycolysis, which is associated with an increase in glucose consumption, lactate production and an increased intracellular ratio of nicotinamide adenine dinucleotide (NAD+/NADH) (Cheng et al. 2014).

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