Trained immunity

"Trained immunity" (TI) or "innate immune memory" is a term for a new immunological concept that describes the ability of an organism to develop an increased responsiveness to secondary stimuli independently of adaptive immunity.

The mechanisms underlying innate immune memory have been extensively studied in recent decades, but remain largely unknown. Although the specificity of adaptive immune memory in vertebrates is provided by recombination of immunoglobulin family genes and clonal expansion, the basic mechanisms of non-specific enhanced responsiveness of innate immune cells rely on epigenetic, transcriptional and metabolic programs following transient stimulation. Changes in these programs lead to increased responsiveness to secondary challenges from a variety of stimuli. This phenomenon is referred to as "trained immunity" or "innate immune memory".

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.

TI was first discovered in cells of the innate immune system, e.g. in monocytes, macrophages and natural killer cells.

Tissue resident memorycells (TRMs) are also tissue-resident CD4+ memory T cells that provide local protection against infections (and tumors). Tissue resident T cells (TRM cells) arise as specialized memory cells through infections and are therefore part of the TI.

However, TI 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).

1. Hamada A et al. (2018) Trained Immunity Carried by Non-immune Cells. Front. Microbiol 9: 3225.
2. Naik, S et al. (2017) Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550: 475-480.
3. Piipponen M et al.(2020) The Immune Functions of Keratinocytes in Skin Wound Healing. Int J Mol Sci 21:8790.
4. Domínguez-Andrés J et al. (2023) Trained immunity: adaptation within innate immune mechanisms. Physiol Rev 103:313-346.