Mast cells (MCs) are evolutionarily old immune cells, of which humans have 2 largely different types. One is a constitutive component of nonepithelial compartments, e.g., the dermis of the skin or submucosal tissues. These cells originate from fetal progenitors and are self maintained in adult steady-state tissue. They are called MCTCs because their secretory granules contain tryptase and chymase (along with cathepsin G and carboxypeptidase). They associate with connective tissue structures, nerves, and blood vessels. Tissue inflammation can result in some increase of MCTC densities. The second population, MCT, expressing tryptase but no chymase, are cells of smaller size, primarily located within barrier epithelia. These cells have received less attention for two reasons: (a) they fail to stain reliably by some metachromatic dyes (which readily identify MCTCs) and (b) they are sparse in steady-state epithelia. However, they rapidly expand into large populations under the influence of inflammation. In this issue of the JCI, Derakhshan et al. (1) report on TGF-β–driven differentiation of inflammatory MCTs, which are likely pathogenic in chronic airway disease (Figure 1).

TGF-β directs differentiation of inflammatory intraepithelial MCs in NP. Steady-state nasal mucosa contains few MCT within the respiratory epithelium or in glandular epithelial structures. In CRS, chronic exposure to pathogenetic factors compromises epithelial homeostasis and triggers subepithelial eosinophilic type 2 inflammation. Inflammatory stimuli drive expansion of intraepithelial MCTs into a large population by proliferation of MMCs and recruitment of bone marrow–derived MC progenitors (MCp). The findings of Derekhshan et al. (1) suggest that stress or damage results in enhanced expression of TGF-β by epithelial cells. TGF-β drives differentiation of an inflammatory MCT phenotype (iMCT) with expression of CPA3, IL-5, and increased production of cysteinyl leukotrienes (Cys-LT). MCT-derived factors may be key for initiating and/or sustaining the pathogenic type 2 inflammation and hyperplasia of epithelial and stromal compartments.

Much of our knowledge about human MCTs has been inferred from investigation of their murine equivalent, mucosal MCs (MMCs). The dependence of their presence on inflammatory stimulation is underpinned by their absence in T cell–deficient mice and humans and in germ-free mice. Type 2 inflammation, as in intestinal helminth infection or allergic airway disease, triggers rapid and dramatic IL-4–dependent increases in MMC numbers. While recruitment of hematopoietic stem cell–derived progenitors was considered the major mechanism of this expansion (2), local proliferation also contributes substantially (3). When inflammation ceases and the barrier tissue returns to homeostasis, MMC numbers slowly decline, which may be due to a differentiation program with ultimate downregulation of the growth factor tyrosine kinase receptor KIT that reduces stem cell factor survival signals (2).