Distribution and storage of inflammatory memory in barrier tissues


Memories of previous immune events enable barrier tissues to rapidly recall distinct environmental exposures. To effectively inform future responses, these past experiences can be stored in cell types that are long-term residents or essential constituents of tissues. There is an emerging understanding that, in addition to antigen-specific immune cells, diverse haematopoietic, stromal, parenchymal and neuronal cell types can store inflammatory memory. Here, we explore the impact of previous immune activity on various cell lineages with the goal of presenting a unified view of inflammatory memory to environmental exposures (such as allergens, antigens, noxious agents and microorganisms) at barrier tissues. We propose that inflammatory memory is distributed across diverse cell types and stored through shifts in cell states, and we provide a framework to guide future experiments. This distribution and storage may promote adaptation or maladaptation in homeostatic, maintenance and disease settings — especially if the distribution of memory favours cellular cooperation during storage or recall.

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Fig. 1: Cell type residence and permanence in barrier tissues.
Fig. 2: Properties of tissue inflammatory memory storage.
Fig. 3: Inflammatory memory alters circuits in barrier tissues.
Fig. 4: Distribution and cooperation in tissue memory.


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The authors thank the following individuals for insightful discussions and comments: S. Nyquist, M. Vukovic, S. Kazer, M. Ramseier, V. Miao, C. Kummerlowe, S. Prakadan, E. Christian, A. Hornick, members of the Shalek laboratory, U. von Andrian, C. Borges, Z. Sullivan, V. Mani and S. Naik. This work was supported, in part, by the Damon Runyon Cancer Research Foundation (Howard Hughes Medical Institute Fellow DRG-2274-16; to J.O.-M.), the Richard and Susan Smith Family Foundation (to J.O.-M.), the Searle Scholars Program (to A.K.S.), the Beckman Young Investigator Program (to A.K.S.), the Pew–Stewart Scholars Program for Cancer Research (to A.K.S.), a Sloan Fellowship in Chemistry (to A.K.S.), the US National Institutes of Health (1DP2GM119419, 2U19AI089992, 2R01HL095791, 1U54CA217377, 2P01AI039671, 5U24AI118672, 2RM1HG006193, 1U2CCA23319501, 1R01AI138546, 1R01HL134539 and 1R01DA046277; to A.K.S.), the US Food and Drug Administration (HHSF223201810172C; to A.K.S.) and the Bill and Melinda Gates Foundation (to A.K.S.).

Author information

J.O.-M. contributed to researching the data for the article, discussion of content, and writing and editing the manuscript before submission. A.K.S. contributed to discussion of content, and writing and editing the manuscript before submission. S.B. and S.R.-N. contributed to discussion of content and editing of the manuscript before submission.

Correspondence to Jose Ordovas-Montanes.

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Competing interests

A.K.S. has received compensation for consulting and SAB membership from Honeycomb Biotechnologies, Cellarity, Cogen Therapeutics and Dahlia Biosciences. All other authors declare no competing interests.

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Nature Reviews Immunology thanks A. Iwasaki, G. Natoli, M. Netea and D. Masopust for their contribution to the peer review of this work.

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Barrier tissues

Epithelial tissues that interface directly with the external environment (that is, any surface directly and constantly exposed to the world outside the host), composed of a monolayer, pseudo-stratified or stratified epithelium, as well as an underlying stromal-derived component and other transient, resident or permanent resident cell lineages.

Immune event

Exposure to an environmental stimulus (such as allergens, antigens, noxious agents, diet, pathogens and microbial communities) or a host-derived stimulus (such as metastasis or sterile tissue damage) at a barrier tissue sensed by the host, triggering downstream transcription and/or epigenetic changes in cell state and/or cell composition in the tissue.


The properties of memory include an altered baseline, sensitivity, rapidity or maximum for a defined response upon secondary challenge to an initiating trigger.

Adaptive immune memory

Classically defined as a memory response by a cell that is considered part of the adaptive immune system (for example, T cells and B cells), based on the ability of its receptor to be formed through the recombination of genetic elements and stably inherited across cell divisions.

Cell types

Developmentally specified cell identity modules that are typically irreversible beyond enforced overexpression of lineage-overriding transcription factors.

Cell subsets

Typically developmentally stable cells, but their programming may be overridden based on niche availability or extreme environments.

Cell state

Characteristics that can be transiently acquired from tissue entry and/or an immune event, are distinct from cellular differentiation and are related to the quality (that is, type of inflammation) of an immune response.

Gene modules

Sets of co-varying genes that may be co-regulated through the activity of one or more transcription factors, or a complex thereof, often associated with a specific cell attribute such as cell type (T cell) or cell state (forkhead box P3 (FOXP3)+ regulatory T cell).

Inflammatory memory

A memory response by any cell lineage to an environmental or host-derived cue, typically acquired during an immune event.

Protective immunological memory

A functionally defensive memory response that enables the host to better respond to secondary challenge after an initial exposure. This function can comprise any of the potential mechanisms that may mediate protective recall, and these same mechanisms may concomitantly or separately mediate immunopathology.

Innate immune memory

Classically defined as a memory response by a cell that is considered part of the innate immune system (for example, macrophages and natural killer cells). However, we favour the use of innate immune memory for memory events triggered by germline-encoded receptors expressed by any cell lineage.

Lipopolysaccharide (LPS) tolerance

Macrophages exposed to sustained stimulation with LPS or high-dose LPS acquire a hypo-responsive state in which sets of inflammatory genes are blunted in their secondary response to LPS or other inflammatory cytokines.

Tuft cells

Rare chemosensory epithelial cells with a ‘tuft-like’ brush of microvilli present in epithelial (primarily mucosal) tissues of mammals, characterized by expression of taste receptors and production of instructive allergic inflammatory cytokines.

Dendritic epidermal T cells

γδ T cell receptor-expressing cells selectively localized in the epidermis that have been identified in rodents and cattle, but not in humans. In mice, essentially all dendritic epidermal T cells express the same T cell receptor constituting a prototypical innate-like T cell.

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Ordovas-Montanes, J., Beyaz, S., Rakoff-Nahoum, S. et al. Distribution and storage of inflammatory memory in barrier tissues. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-019-0263-z

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