Trained immunity: A program of innate immune memory in health and disease

Abstract

The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity, as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed "trained immunity" or "innate immune memory." Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, new therapeutic strategies for the treatment of immune deficiency states, and modulation of exaggerated inflammation in autoinflammatory diseases.

Figure 1

A. Classical adaptive immunological memory involves gene recombination in B- and T-lymphocytes, which confers high specificity and very often long-term, pathogen-specific protection (up to decades). B. Trained immunity defines a de-facto innate immune memory that induces enhanced inflammatory and antimicrobial properties in innate immune cells, responsible for an increased non-specific response to subsequent infections and improved survival of the host.

Figure 2

Epigenetic rewiring underlies the adaptive characteristics of innate immune cells during trained immunity. Initial activation of gene transcription is accompanied by the acquisition of specific chromatin marks, which are only partially lost after elimination of the stimulus. The enhanced epigenetic status of the innate immune cells, illustrated by the persistence of histone marks such as H3K4me1 characterizing ‘latent enhancers’, results in a stronger response to secondary stimuli upon re-challenge.

Figure 3

Stimulation of innate immune cells with training stimuli induces changes in cellular metabolism. Various metabolites function as co-factors for epigenetic enzymes, which in turn induce chromatin and DNA modifications, modulate gene transcription and result in different trained immunity programs.