Elsevier

Immunobiology

Volume 212, Issue 6, 27 June 2007, Pages 505-519
Immunobiology

Mast cells in allergy: Innate instructors of adaptive responses

https://doi.org/10.1016/j.imbio.2007.03.012Get rights and content

Abstract

The function of mast cells as effector cells in allergy has been extensively studied. However, increasing insight into mast cell physiology has revealed new mast cell functions and has introduced mast cells as key players in the regulation of innate as well as adaptive immunity. For example, mast cells have recently been found to express Toll-like receptors (TLRs), which enable them to participate in the innate immune response against pathogens. Furthermore, mast cells have been reported to interact with B cells, dendritic cells and T cells and thereby modulate the direction of an adaptive immune response. Finally, recent documentation that mast cells express functional MHC class II and costimulatory molecules and release immunologically active exosomes, has raised the possibility that mast cells also engage in (as yet) poorly understood antigen presentation functions. In this review, we explore the hypothesis that mast cells serve as central mediators between innate and adaptive immunity, rather as pure effector cells, during allergic innate responses.

Introduction

When Paul Ehrlich as a 24-year-old student presenting his doctoral thesis in 1878, described a type of “granular cells of the connective tissue”, which he named “Mastzellen” (Riley, 1954; Vyas and Krishnaswamy, 2006), he was inaugurating a vivid and multidirectional research to explore the development, phenotype, physiology and pathophysiology of these cells.

Since then, the universe of mast cell biology has been ever extending and the deeper we explore the biology of these fascinating cells, the more functions we discover, including some that shatter long-held beliefs on their nature and limitations (Maurer et al., 2003; Maurer and Metz, 2005).

Initially, mast cells were primarily connected to the anaphylaxis reaction (Keller, 1962). Later they were given the role of “effector cells” in allergy (Williams and Galli, 2000) and for years the main focus of mast cell-related research was their histamine-containing metachromatic granules (Riley and West, 1952) and their high-affinity immunoglobulin (Ig) E receptor FcεRI (Metzger, 1992; Turner and Kinet, 1999). The resulting degranulation with release of histamine and inflammatory cytokines after crosslinking of FcεRI by IgE and antigen has been extensively correlated with the physiological role of mast cells, to the extent of mast cells being mainly referred to as effector cells in the allergic immune response.

More than a century passed before mast cells were attributed a crucial role in host defense and establishment of the innate immunity (Echtenacher et al., 1996; Malaviya et al., 1994, Malaviya et al., 1996a). Since then, the focus on mast cells has broadened towards the investigation of their phenotypical and functional characteristics that enable them to participate in the establishment of innate immunity. And, it has been only during the last two decades that a contribution of mast cells in the initiation of adaptive immune responses has been appreciated (Banovac et al., 1989a, Banovac et al., 1989b; Fox et al., 1994; Frandji et al., 1993; Grabbe et al., 1997).

Thus, nowadays, mast cells are recognized not only as “granular cells of the connective tissue” (Riley, 1954), whose activation exacerbates allergic immune responses, but also as key players in the establishment of innate immunity as well as modulators of adaptive immune responses.

During the first 100 years after Paul Ehrlich first mentioned them, mast cells were believed to be a component of the connective tissue. Only in the 1970s it was proved that they derive from hematopoietic stem cells (Kitamura et al., 1977; Nabel et al., 1981). Mast cell-committed precursors, defined by the phenotype Thy-1low c-kithigh FcεRIαlow and described in fetal murine liver, are able to generate functionally competent mast cells in vivo (Rodewald et al., 1996). Mast cell progenitors in the bone marrow of adult mice are phenotypically Lyn c-kit+ Sca-1 Ly6c FcεRIα CD27 β7+ T1/ST2+ and derive directly from multipotent rather than from common myeloid progenitor cells (Chen et al., 2005). After homing into different tissues, mast cell progenitors differentiate into mature, long-lived, phenotypically diverse mucosal or connective tissue mast cells. Mast cell progenitors are either committed to a distinct subtype, and selectively recruited to the tissue, or get a tissue-specific character after epigenetic influence by environmental factors (Tsai et al., 2005).

c-kit plays a major role in mast cell differentiation and mast cell functions. Mice with c-kit loss of function mutations lack mast cells in contrast to mice deficient for interleukin (IL)-3, which exhibit only marked reduction of mast cell hyperplasia induced by parasites (Lantz et al., 1998). Two most frequently used mast cell-deficient mice strains are WBB6F1-KitW/KitW-v and KitW-sh/KitW-sh mice (C57BL/6 genetic background).

Double heterozygote mice WBB6F1-KitW/KitW-v bear two distinct mutations at the white spotting (W) locus. This locus on chromosome 5 encodes the stem cell factor (SCF) receptor c-kit (CD117). Point mutation resulting in threonine to methionine substitution on KitW-v allele and deletion mutation of 78 amino acids resulting in the absence of the transmembrane domain on the KitW allele, lead to an abnormal development and a decreased survival of mast cells. Therefore, WBB6F1-KitW/KitW-v mice are mast cell deficient and commonly used for studies of different immune reactions in the absence of mast cells (Galli and Kitamura, 1987; Tsai et al., 2005). However, this strain carries different additional abnormalities, caused by the lack of c-kit function, such as macrocytic anemia, lack of melanocytes, intestinal TCRγδ intraepithelial lymphocytes and interstitial cells of Cajal and sterility. Additionally, complex and long-lasting breeding strategies make this strain not very suitable for crossing with knockout mice to study the role of different cell surface molecules or cytokines in regulation of mast cell function in vivo.

Another mouse strain lacking mast cells, KitW-sh/KitW-sh mice, bear an inversion mutation in transcriptional regulatory elements upstream of the c-kit transcription start (Berrozpe et al., 1999) leading to tissue-type specific dysregulation of c-kit expression. Mice of this strain have white coat color and black eyes and almost complete lack of tissue mast cells. However, they are neither anemic nor sterile, they have normal numbers of TCR γδ IELs and do not exhibit a spontaneous pathology in the skin, stomach or duodenum (Grimbaldeston et al., 2005). This strain can be used to produce mast cell-deficient mice that additionally are deficient (knockout) or constitutively express particular genes (transgenic). After reconstitution with mast cells generated either from bone marrow or embryonic stem cells or isolated directly, e.g. from peritoneal cavity, mice are used to investigate how mast cells function in an environment with such deficiency or constitutive expression (Nakano et al., 1985).

The immune responses in contact hypersensitivity (CHS) and delayed type hypersensitivity (DTH) reactions, and production of ovalbumin (OVA)-specific IgE and IgG1 after sensitization and challenge with aerosolized OVA are comparable in WBB6F1-KitW/Kit W-v and WBB6F1-Kit+/+ mice (Ha et al., 1986; Ha and Reed, 1987; Kung et al., 1995; Mekori and Galli, 1985; Thomas and Schrader, 1983). However, results from functional comparisons of mast cell-mediated effects on multiple cellular players should be interpreted carefully at least for two reasons: first, due to the essential role of c-kit in lymphopoiesis (Agosti et al., 2004; Waskow et al., 2002), illustrated e.g. by reduction of percentage of CD25+ cells in thymus (Waskow et al., 2002) and second, because some inflammatory conditions could induce SCF-independent mast cell development (Galli et al., 1987; Gordon and Galli, 1990). Therefore, generation of new mouse strains exclusively deficient in mast cells will be an important task for future investigations.

Section snippets

Mast cells in host defense

Mast cells are commonly found at sites exposed to the external environment, namely the skin, the airways and the gastrointestinal tract (Galli et al., 1999; Marshall, 2004). At such places mast cells are capable of encountering antigens of the external environment, therefore playing an important role in the recognition and defense against invading microorganisms and the establishment of innate immunity. So far, mast cells are recognized mediators of host defenses against parasitic worms and

Toll-like receptors and mast cells

At the center of the detection mechanisms for invading microorganisms in vertebrates, lies the family of Toll-like receptors (TLRs). Similar to the Toll proteins of Drosophila and highly conserved during evolution, the TLR family has been extensively studied both in human and mouse (Gay and Keith, 1991; Medzhitov et al., 1997; Rock et al., 1998). TLRs are expressed by antigen-presenting cells, in order to enable them to recognize and initiate an adaptive immune response leading to the

Mast cells as modulators of T cell responses

Apart from their dominant contribution to the establishment of an innate immune response, mast cells are considered to be important participants also in the regulation of adaptive immunity (Galli et al., 2005). The recent shift in mast cell paradigms has transformed the role of mast cell from a pure protagonist in the effector phase of allergy to a main player in the interphase between innate and adaptive immunity. Further, mast cells control the phenotype and function of the adaptive immunity

Conclusions

In this review, we have summarized the available evidence that apart from their prominent and well-documented role as effector cells in allergy, mast cells play a significant role in the establishment of innate as well as adaptive immune responses. The expression of molecules, which have been correlated with the innate (TLRs) and with the adaptive (MHC class II and costimulatory molecules) immune signalling, suggests that mast cells are capable of acting as regulators of both innate and

Acknowledgments

The authors would like to thank Dr. Annalena Bollinger and Dr. Rene Rückert for critical reading of the manuscript.

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