Mast cells (MCs), tissue-resident immune effector cells that predate the evolution of adaptive immunity (1, 2), were first identified by Paul Erlich as part of his doctoral thesis work. Erlich described a cell with abundant granules that reacted metachromatically to methylated blue dye, noting that these cells were often found near blood vessels and observed across a broad range of tissues. Erlich hypothesized that these cells arose from connective tissue and played a role in feeding neighboring cells. Over nearly a century of subsequent research, MCs were found to be a major tissue source of histamine (3), contain a range of proteases (4, 5), and respond to IgE cross-linking by releasing histamine, slow-reacting substance of anaphylaxis (6) (now better known as the cysteinyl leukotrienes), and PGD2 (7), explaining the elevated PGD2 levels observed in systemic mastocytosis patients (8).

Through a series of careful histologic studies, Enerbäck definitively identified distinctions between MC across tissues, characterizing distinct staining properties of rat connective tissue MCs (CTMCs) and mucosal MCs (MMCs) that he correctly hypothesized were related to differences in the proteoglycan structure of MC granules across these two subsets (912). In a subsequent study, Enerbäck and Löwhagen (13) determined that compound 48/80, a pharmacologic MC degranulating agent now known to act through the mas-related G protein–coupled receptor (MPGPR) family (14, 15), leads to degranulation of CTMCs and a rapid accumulation of intestinal MMCs. For rat MMCs, there was a half-life of ∼40 d (13). In contrast to the dynamic expansion and contraction of MMCs, radiolabeling studies indicated that mouse CTMCs within the skin, tongue, and footpad were extraordinarily stable, with an estimated turnover rate of 9–18 mo (16).

Despite significant advances in understanding the roles these MCs played in allergic tissue inflammation, the ontologic origin of MCs remained poorly understood. The prevailing theory was that MCs were mesenchymal in origin, whereas others had proposed that MCs were derived from lymphocytes, plasma cells, or mononuclear progenitors with basophilic granules (17). The two articles featured in this Pillars of Immunology commentary initially set out to answer this basic question of MC origin. In the first, Kitamura et al. (18) evaluated the potential for MCs to arise from the bone marrow (BM) (https://www.nature.com/articles/268442a0). To do this, they took advantage of Beige mice, a strain on the C57/BL background in which MCs have giant granules and can be readily distinguished from C57BL wild-type (WT) MCs (19). Kitamura et al. (18) conducted a BM transplant following irradiation and assessed the appearance of MCs with giant granules (e.g., BM donor derived) at a series of timepoints across five tissue types. In doing so, the authors observed that within 63 d, MCs in the cecum and glandular stomach predominantly contained giant granules, whereas surprisingly negligible numbers of donor-derived MCs were seen in the mesentery and skin, but the forestomach exhibited an intermediate phenotype. Together, these observations suggested distinct ontologic origins for MMC and CTMC, with MMC arising from the BM and a separate origin for radioresistant CTMCs.

In the second Pillars of Immunology article, Kitamura et al. (20) describe the W/Wv mouse strain, in which MCs were virtually absent from the skin and stomach (https://www.sciencedirect.com/science/article/pii/S000649712068288X). When these MC-deficient mice received a BM transplant from WT mice, donor-derived MCs were subsequently observed across all five tissues evaluated in the prior study. MC concentrations in the mesentery of reconstituted W/Wv mice approached the baseline levels seen in WT mice, whereas only a partial reconstitution was seen in the skin. The findings from these two studies argued against a mesenchymal origin of MCs, identified the differential contribution of BM to the maintenance of CTMC and MMC populations, and suggested that resident MCs blocked the colonization of connective tissues by BM-derived progenitors. These studies additionally established an MC-deficient strain that would be used to identify, among many other pleiotropic functions, discrete protective roles for BM-derived inflammation-expanded MMC in helminth rejection and constitutive CTMCs in xenobiotic venom detoxification (21, 22).

The understanding that MMCs were BM derived quickly led to a series of advances in our understanding of MC hyperplasia during Th2 inflammation. After using parabiosis to demonstrate that peripheral blood–derived precursors contributed to the maintenance of MMC at steady-state, especially in the cecum (23), Kitamura et al. developed a limited dilution and clonal expansion assay to characterize MC progenitor (MCp) concentration within the BM and peripheral blood (24). This assay was subsequently adapted by Crapper and Schrader to study the concentration of MCp in mucosal tissues, identifying an enormous pool of “invisible” progenitors across tissues (25). Gurish et al. (26) then identified a critical role for β7 integrin in the constitutive homing of these progenitor cells to the lung and intestine using both genetic deletion of β7 integrin and mAbs directed against both β7 alone and the α4β7 pair, further determining that BM-derived MCp have a half-life of 7 d in normal tissue (26, 27). With the rise of flow cytometry, β7 integrin was used to identify MCp within 1) mesenteric lymph nodes during Trichinella spiralis infection (28), 2) the peritoneum during steady-state (29), and 3) the lung during several models of airway inflammation, where it served to distinguish entry of BM-derived MCp from resident CTMCs in both C57/Bl6 and BALB/c mice (30, 31). In BALB/c, the gradual loss of β7 together with a decrease in Kit expression and increased side angle light scatter, a mark of granulation, could also be used to track MMC differentiation from recruited BM MCp (30). Human circulating MCp similarly express β7 (32), underscoring its use as a marker of MCp across species.

Murine MCs express a broad range of granule-associated proteases, including murine MC protease (mMCp) 1-9, carboxypeptidase A3 (CPA3), granzymes, and cathepsin G (33). The development of Abs directed against these specific MC proteases allowed for the discovery of further distinction between MCs across tissues (3438). Mucosal MCs in the jejunum were found to express a limited repertoire of proteases following T. spiralis–elicited expansion, limited to mMCP-1 and mMCP-2, whereas CTMCs within the same tissue expressed a broader range of proteases (39). In contrast, MMCs in the lung following OVA sensitization and challenge expressed mMCP-6 and mMCP-7 in addition to mMCP-1 and mMCP-2, whereas both MMC and CTMC within the trachea expressed all proteases evaluated (40). Studies with the immature v-abl transformed V3-MC line indicated a direct role for the tissue in regulating the MC protease phenotype, with clonal MCs undertaking discrete protease phenotypes in each tissue to which they engrafted (38).

Transcriptomics analysis would later show a more-subtle, but still distinct, impact of tissue on resident CTMC, identifying three groups (the skin, the peritoneal cavity, and a third group containing MCs from the tongue, esophagus, and trachea), which varied in protease expression levels and cell surface protein expression (41). Although human MCs exhibit a more-limited protease expression profile, protease immunophenotyping would similarly prove useful in differentiating human MC subsets, with MCs in connective tissues coexpressing the proteases tryptase and chymase, whereas those found within the epithelium express tryptase in the absence of chymase (MCT) (42). These phenotypes change in the context of Th2 inflammation: MCT additionally express CPA3 in asthma (43), nasal polyposis (44), and eosinophilic esophagitis (45), whereas MCs expressing chymase expand within the epithelium during severe asthma (46). Furthermore, both MCT and dual tryptase and chymase positive MC within the lung exhibit alterations in cell surface proteins, cytokines, and lipid mediator biosynthetic enzymes based on microenvironment and disease status (47, 48), indicating that the full range of human MC phenotypes is not yet understood.

Kitamura’s 1977 discovery that the BM only made a very limited contribution to the maintenance of MCs in the skin and mesentery indicated that, in contrast to the BM-derived MMC, constitutively present CTMCs must arise earlier in development. Indeed, in a subsequent study, Kitamura was able to identify the presence of MCp within the murine yolk sac and fetal liver during early development, with progenitor concentration highest in the yolk sac until day 11, after which concentration decreased in the yolk sac and transiently increased in the liver (49). This progenitor was later isolated by Rodewald et al. (50), who identified a Thy-1lowc-Kithi cell expressing transcript encoding CPA as well as mMCP-2 and mMCP-4 that were committed to the MC lineage and could reconstitute the peritoneal cavity MC compartment in MC-deficient mice. The relevance of this neonatal progenitor was recently clarified through a pair of lineage tracing studies, independently showing that constitutive CTMCs are seeded in a series of waves (51, 52). A first wave of progenitors arising from primitive hematopoiesis in the yolk sac is replaced during the neonatal window by a wave of progenitors arising from definitive hematopoiesis, which then maintain CTMC population throughout the lifetime of the mouse, without additional contribution from the BM.

More recently, the Roers laboratory showed that these neonatally derived MCs establish stable clonal “territories” within the skin, from which circulating progenitors are excluded during homeostatic conditions (53). However, following the induction of tissue inflammation, these territories break down, allowing the infiltration of progenitors from the BM. Similarly, epicutaneous sensitization to OVA elicits an ILC2-dependent, microbiome-independent expansion of submucosal MCs in the jejunum of both of C57/Bl6 and BALB/c mice, suggesting a broader paradigm of inflammation “licensing”—the maturation of BM-derived progenitors in connective tissue compartments (54, 55). Thus, although resident CTMCs are innate in origin, the inflammation-associated expansion of MMC and CTMC following recruitment of BM-derived MCp reflects their tissue-directed phenotype.

Kitamura’s early studies of MC development have had enormous influence within the MC field. His observations led directly to our current understanding that the innate CTMC and induced MMC are, in fact, distinct lineages with separate developmental pathways (51, 52), with recent studies suggesting that these subsets additionally have separate influences on tissue inflammation (31). The understanding that MCs could arise directly from the BM and the development of assays to measure these “invisible” MCs shepherded discoveries reflecting the abilities of MCs to sense local tissue microenvironments and take on a broad range of phenotypes, likely tailored toward local needs. The innate CTMC lineage, to which the BM did not contribute, is now understood to arise from early neonatal progenitors that maintain CTMCs through adulthood, in part, through enforcing discrete territories (5153). Thus, a direct line can be drawn from the initial suggestion of multiple MC lineages presented in these two Pillars of Immunology studies to the cutting-edge research being conducted in the present day.

K. Frank Austen is a Distinguished Fellow of AAI.

Abbreviations used in this article

     
  • BM

    bone marrow

  •  
  • CTMC

    connective tissue MC

  •  
  • MC

    mast cell

  •  
  • MCp

    MC progenitor

  •  
  • MCT

    MC expressing tryptase

  •  
  • MMC

    mucosal MC

  •  
  • mMCp

    murine MC protease

  •  
  • WT

    wild-type

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The authors have no financial conflicts of interest.