New and emerging roles for mast cells in host defence

doi:10.1016/j.coi.2006.11.006

Current Opinion in Immunology

Volume 19, Issue 1, February 2007, Pages 31-38

https://doi.org/10.1016/j.coi.2006.11.006 Get rights and content

Mast cells are highly effective sentinel cells, found close to blood vessels and especially common sites of potential infection, such as the skin, airways and gastrointestinal tract. Mast cells participate actively in the innate immune responses to many pathogens through a broad spectrum of mediators that can be selectively generated. They also have a role as innate effector cells in enhancing the earliest processes in the development of acquired immune responses. Studies of bacterial and parasitic models have revealed mast cell dependent regulation of effector cell recruitment, mucosal barrier function and lymph node hypertrophy. An important role for mast cells in viral infection is also implied by several in vivo and in vitro studies. There are multiple direct and indirect pathways by which mast cells can be selectively activated by pathogens including Toll-like receptors, co-receptors and complement component receptors. Understanding the mechanisms and scope of the contribution of mast cells to host defence will be crucial to regulating their activity therapeutically.

Introduction

Mast cells have been most intensively studied in the context of allergic disease, and substantial progress has been made in developing approaches to limit their impact in diseases such as allergic asthma and rhinitis. Mast cells are strategically located at sites that interface with our external environment, closely associated with blood vessels and nerves. As long-lived cells, they can have an enormous impact on the tissue microenvironment through the selective release of a wide variety of preformed and newly derived mediators including potent proteases, cytokines, chemokines and arachidonic acid metabolites. Their important role in response to certain parasite infections is well accepted. Over recent years, however, the contribution of mast cells to many other aspects of host defence has become recognized [1, 2, 3]. Rapidly activated by a variety of mechanisms in response to bacterial infection, they can be crucial for the early recruitment of effector cells such as neutrophils. During certain viral infections, mast cells might also be an important early source of selected cytokines and chemokines. Recent studies suggest a complex role for mast cells in regulating both the nature and the intensity of immune responses to infection [4, 5], including modulation of both dendritic cell and T-cell responses.

In this review, we will focus on mast cells outside the context of allergic disease and will examine recent progress in understanding the role of the mast cell in host defence. Advances in awareness of their capacity as effector cells of the innate immune response and as important regulators of the development of acquired immunity will be highlighted.

Section snippets

Improved models to study mast cells in innate immunity

In vivo studies of responses to infection using the mast cell deficient W/Wv mouse model provided the earliest compelling evidence of the role of mast cells in host defence [6, 7]. W/Wv mice are deficient in mast cells owing to the reduced function of c-kit, which is essential for mast cell development and survival. More recently, the Wsh/Wsh mast cell deficient mouse model, which also has reduced c-kit function, has provided further opportunities to study the role of mast cells [8^•]. These

Bacterial infection

Mast cells have been implicated in host defence against an increasing range of clinically relevant bacterial infections. In the Citrobacter rodentium murine experimental model of human enteropathogenic E. coli infection mast cell deficient mice demonstrated decreased survival and increased systemic bacterial dissemination [13]. Similarly, mast cell deficient W/Wv mice were found to be unprotected from Helicobacter felis colonization after immunization [14]. In both cases, reconstitution with

Mobilization of the early acquired immune response

The role of the mast cell as a sentinel cell for the initial recruitment of effector cells is well established. However, the concept that mast cell responses trigger a cascade of events that enhance subsequent acquired immune responses is still the subject of some debate. Studies of mast cell mediated dendritic cell (DC) maturation and migration, lymph node hypertrophy, and T-cell migration and activation lend support to idea that mast cells can initiate many key processes in the generation of

Complement pathway interactions with mast cells

Complement activation is a hallmark of early innate responses to many infections. Mast cells have several complement receptors, for example C3a receptor, C5a receptor, complement receptor 2, complement receptor 4 and complement receptor 5, and interaction of these receptors with aspects of the complement pathway can be crucial to their role in innate immunity [53, 54] and also could impact on mast cell dependent mobilization of DCs [39^•]. Collectins, which include mannose-binding lectin (MBL),

Toll-like receptor and co-receptor mediated activation of mast cells

Both human and rodent mast cells can express a wide range of TLRs. Some are expressed only on certain mast cell subsets, although cytokine microenvironments can profoundly alter the expression of others. Analysis of TLR expression profiles of fetal skin derived mast cells (FSMCs) and mBMMCs revealed that the two mast cells populations differ significantly in their responses to TLR agonists. FSMCs expressed much higher levels of TLR3, TLR7 and TLR9 than mBMMCs, and ligation of these TLRs drove

Conclusions

The unique role of the mast cell lies in their location, resident at sites of pathogen exposure, and in the potency, rapidity and selectivity of mediator production in response to pathogens. Many mediators are produced locally within minutes of infection, whereas sustained local production of cytokines and chemokines provide a potent stimulus for effector cell recruitment and the earliest stages of initiation of acquired immunity. It is important to remember that mast cells in vivo might be

Update

Recently, Lu et al. [77] have shown that mast calls have a crucial role in regulatory T cell (T_reg) mediated allograft tolerance. Injection of allogeneic cells in the presence of blocking anti-CD154 antibody allows for the long-term acceptance of allogeneic skin grafts. In addition to increases in T_reg, mast cell numbers were elevated in the tolerized grafts. Tolerance was not induced in mast cell deficient mice, and local reconstitution with mast cells extended graft survival by mechanisms

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

The authors would like to thank The Canadian Institutes of Health Research for the support of their research program.

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View full text

New and emerging roles for mast cells in host defence

Introduction

Section snippets

Improved models to study mast cells in innate immunity

Bacterial infection

Mobilization of the early acquired immune response

Complement pathway interactions with mast cells

Toll-like receptor and co-receptor mediated activation of mast cells

Conclusions

Update

References and recommended reading

Acknowledgements

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Am J Pathol

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Infect Immun

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Characterization of novel stem cell factor responsive human mast cell lines LAD 1 and 2 established from a patient with mast cell sarcoma/leukemia; activation following aggregation of FcɛRI or FcγRI

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Pseudomonas aeruginosa exotoxin A induces human mast cell apoptosis by a caspase-8 and -3-dependent mechanism

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Release of vasoactive cytokines by antibody enhanced dengue virus infection of a human mast cell/basophil line

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