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New perspectives on the origins and heterogeneity of mast cells

Abstract

Mast cells are immune cells of the haematopoietic lineage that are now thought to have multifaceted functions during homeostasis and in various disease states. Furthermore, while mast cells have been known for a long time to contribute to allergic disease in adults, recent studies, mainly in mice, have highlighted their early origins during fetal development and potential for immune functions, including allergic responses, in early life. Our understanding of the imprinting of mast cells by particular tissues of residence and their potential for regulatory interactions with organ systems such as the peripheral immune, nervous and vascular systems is also rapidly evolving. Here, we discuss the origins of mast cells and their diverse and plastic phenotypes that are influenced by tissue residence. We explore how divergent phenotypes and functions might result from both their hard-wired ‘nature’ defined by their ontogeny and the ‘nurture’ they receive within specialized tissue microenvironments.

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Fig. 1: The origins of mast cells predate the adaptive immune system.
Fig. 2: Mast cell ontogeny in the developing mouse fetus.
Fig. 3: Sensitization of fetal mast cells by maternal IgE.
Fig. 4: Mast cell interactions with the microenvironment during host defence, inflammation and immune diseases.

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Acknowledgements

The authors acknowledge funding from Duke-NUS Medical School, the Singapore Ministry of Education (MOE2019-T2-1-146, MOE-T2EP30120-0011 and MOET32020-0002) and the National Research Foundation of Singapore (NRF-CRP17-2017-04) to A.L.S., and Singapore Immunology Network core funding, the Singapore BMRC Use-Inspired Basic Research (UIBR) Award and the Singapore National Research Foundation Senior Investigatorship (NRF2016NRF-NRFI001-02) to F.G.

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Glossary

Aorta–gonad–mesonephros

An area containing the aorta, urogenital ridges and mesonephros found at the posterior end of a developing embryo, where definitive haematopoiesis begins.

Corneal limbus

A highly vascularized and pigmented zone between the cornea and sclera of the eye.

Definitive haematopoiesis

The generation of multipotent haematopoietic stem cells derived from the aorta–gonad–mesonephros, which can give rise to all blood cell lineages.

Interstitial cells of Cajal

The mesenchymal cells present in the gastrointestinal tract known for their role in gut motility.

‘Nature’ versus ‘nurture’

In the historical debate relating to the inheritance of traits, ‘nature’, a hardwired form of inheritance now understood to be associated with genetic inheritance, was seen as a contrasting hypothesis to ‘nurture’, the shaping of traits by the environment.

Non-peptidergic nerves

Somatosensory C fibres that bind to isolectin B4 and express the G protein-coupled receptor MRGPRD.

Peptidergic nerves

Somatosensory C fibres that express neuropeptides, substance P and calcitonin gene-related peptide, and that do not bind isolectin B4.

Primitive haematopoiesis

The first wave of haematopoiesis during development marked by the production of large nucleated embryonic erythrocytes and some early erythroid–myeloid progenitor cells from the blood islands in the yolk sac, beginning at embryonic day 7 in mice.

Pseudoallergy

A non-allergic anaphylactic reaction that occurs in the absence of antigen-specific immune responses. Some of the common pseudoallergens include antibiotics and nonsteroidal anti-inflammatory drugs.

Transient definitive haematopoiesis

The production of progenitors of the erythroid–myeloid lineage that have limited proliferative capacity and are derived from the yolk sac.

Type 1 immune response

A type of polarized immune response that is characterized by enhanced phagocytic activity together with increased production of interferon-γ, IL-2 and tumour necrosis factor (TNF), and provides protection against intracellular pathogens, including bacteria and viruses.

Type 2 immune response

A type of polarized immune response that is characterized by increased production of the cytokines IL-4, IL-5, IL-9 and IL-13, and is frequently associated with allergic inflammation or parasitic infection.

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St. John, A.L., Rathore, A.P.S. & Ginhoux, F. New perspectives on the origins and heterogeneity of mast cells. Nat Rev Immunol (2022). https://doi.org/10.1038/s41577-022-00731-2

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