Epithelial-derived TGF-β regulates the development of intraepithelial mast cells during type 2 inflammation

Tahereh Derakhshan, PhD
Department of Medicine
Division of Rheumatology, Immunology, and Allergy
Poster Overview

Mast cells (MCs) are immune cells that expand in the airway, esophagus, and intestine during allergic disease. These expanded MCs are very different from those found in healthy individuals. In mice, TGF-β is a signal produced by epithelial cells that plays a role in the development of allergy-expanded MCs within the epithelium, but the factors controlling the development of these MCs in humans are unknown. We screened the transcriptome of MCs in nasal polyps and found signals that suggests for a role of TGF-β in the development of MCs, so we experimentally tested TGF-β on cord blood-derived MCs. When MCs were stimulated with TGF-β, the expression level of transcripts associated with allergy-expanded MCs within the epithelium were increased, while in contrast, the expression of transcripts associated with MCs residing in other compartments were decreased. When MCs were either directly stimulated with TGF-β or grown with epithelial cells, they became similar to allergy-expanded MCs in patients, while this effect was reduced when signaling through the receptor for TGF-β on MCs was blocked. Therefore, our findings suggest for a role of TGF-β in expansion of MCs during allergic
inflammatory diseases.

Scientific Abstract

Mast cells (MCs) are tissue resident immune effector cells that expand in the epithelium during human type 2 inflammatory diseases. We previously found that in mice, epithelial-derived TGF-β can induce the development of an intraepithelial MC phenotype. However, the factors mediating intraepithelial MC development in humans remain unclear. Here, we hypothesize that epithelial-derived TGF-β plays a similar role in human intraepithelial MC development. To determine the influence of TGF-β on MCs, human umbilical cord blood-derived MCs (CBMCs) were stimulated with TGF-β and analyzed by RNA-sequencing. To assess the specific role of epithelial-derived TGF-β, CBMCs were co-cultured with human nasal epithelial cells in the presence of TGF-β receptor signaling inhibitor and analyzed by flow cytometry. TGF-β stimulus significantly altered MC transcriptome, upregulating a cassette of genes associated with the intraepithelial MC phenotype, including CPA3 and CD38, while downregulating transcripts associated with subepithelial MCs, such as CMA1 and KIT. Epithelial co-culture downregulated MC expression of c-Kit, while upregulated cell surface CD38 and intracellular CPA3 expression, indicative of an intraepithelial MC phenotype. This effect that was attenuated when TGF-β signaling was inhibited suggests for a role of epithelial-derived TGF-β in regulating the development of human intraepithelial MCs during inflammation.

Clinical Implications
Asthma and chronic rhinosinusitis affect nearly 30 million Americans, therefore understanding the disease pathogenesis is crucial. Mast cells are key effector cells during airway inflammation and inhibiting the factors that regulate their development and functional modulations has important therapeutic implications.
Research Areas
Authors
Tahereh Derakhshan, PhD, Chunli Feng, MD, Tanya M. Laidlaw, MD, Joshua A. Boyce, MD, Daniel F. Dwyer, PhD
Principal Investigator
Daniel F. Dwyer

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