Review

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

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Science  22 Apr 2016:
Vol. 352, Issue 6284, aaf1098
DOI: 10.1126/science.aaf1098

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Training immune cells to remember

Classical immunological memory, carried out by T and B lymphocytes, ensures that we feel the ill effects of many pathogens only once. Netea et al.review how cells of the innate immune system, which lack the antigen specificity, clonality, and longevity of T cell and B cells, have some capacity to remember, too. Termed “trained immunity,” the property allows macrophages, monocytes, and natural killer cells to show enhanced responsiveness when they reencounter pathogens. Epigenetic changes largely drive trained immunity, which is shorter lived and less specific than classical memory but probably still gives us a leg up during many infections.

Science, this issue p. 10.1126/science.aaf1098

Structured Abstract

BACKGROUND

Host immune responses are classically divided into innate immune responses, which react rapidly and nonspecifically upon encountering a pathogen, and adaptive immune responses, which are slower to develop but are specific and build up immunological memory. The dogma that only adaptive immunity can build immunological memory has recently been challenged by studies showing that innate immune responses in plants and invertebrates (organisms lacking adaptive immune responses) can mount resistance to reinfection. Furthermore, in certain mammalian models of vaccination, protection from reinfection has been shown to occur independently of T and B lymphocytes. These observations led to the hypothesis that innate immunity can display adaptive characteristics after challenge with pathogens or their products. This de facto immunological memory has been termed “trained immunity” or “innate immune memory.”

ADVANCES

In recent years, emerging evidence has shown that after infection or vaccination, prototypical innate immune cells (such as monocytes, macrophages, or natural killer cells) display long-term changes in their functional programs. These changes lead to increased responsiveness upon secondary stimulation by microbial pathogens, increased production of inflammatory mediators, and enhanced capacity to eliminate infection. Mechanistic studies have demonstrated that trained immunity is based on epigenetic reprogramming, which is broadly defined as sustained changes in transcription programs and cell physiology that do not involve permanent genetic changes, such as mutations and recombination. Histone modifications with chromatin reconfiguration have proven to be a central process for trained immunity, but other mechanisms—such as DNA methylation or modulation of microRNA and/or long noncoding RNA expression—are also expected to be involved. This leads to transcriptional programs that rewire the intracellular immune signaling of innate immune cells but also induce a shift of cellular metabolism from oxidative phosphorylation toward aerobic glycolysis, thus increasing the innate immune cells’ capacity to respond to stimulation. Trained immunity programs have evolved as adaptive states that enhance fitness of the host (e.g., protective effects after infection or vaccination, or induction of mucosal tolerance toward colonizing microorganisms). Proof-of-principle experimental studies support the hypothesis that trained immunity is one of the main immunological processes that mediate the nonspecific protective effects against infections induced by vaccines, such as bacillus Calmette-Guérin or measles vaccination. However, when inappropriately activated, trained immunity programs can become maladaptive, as in postsepsis immune paralysis or autoinflammatory diseases.

OUTLOOK

The discovery of trained immunity has revealed an important and previously unrecognized property of human immune responses. This advance opens the door for future research to explore trained immunity’s effect on disease, for both diseases with impaired host defense, such as postsepsis immune paralysis or cancers, and autoinflammatory diseases, in which there is inappropriate activation of inflammation. These findings have considerable potential for aiding in the design of new therapeutic strategies, such as new generations of vaccines that combine classical immunological memory and trained immunity, the activation of trained immunity for the treatment of postsepsis immune paralysis or other immune deficiency states, and modulation of exaggerated inflammation in autoinflammatory diseases.

Innate immune activation by infections or vaccinations leads to histone modifications and functional reprogramming of cells (such as monocytes, macrophages, or NK cells) termed “trained immunity” or “innate immune memory.”

Trained immunity evolved to lead to adaptive states that protect the host during microbial colonization or after infections. However, in certain situations, trained immunity may result in maladaptive states such as postsepsis immune paralysis or hyperinflammation. miRNA, microRNA.

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.

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