T cell-induced airway smooth muscle cell proliferation via the epidermal growth factor receptor

Allergic asthma is a heterogeneous disease with no curative therapies. T cells infiltrate the airway smooth muscle (ASM) layer and may be implicated in airway remodeling and the increase of ASM mass, a cardinal feature of asthma. The mechanism by which CD4+ T cells drive airway remodeling remains unknown. This study sought to determine the T cell-mediated mechanism ofASMcell proliferation. WehypothesizedthatCD41Tcells adhere toASMcells via CD44, and induce ASM cell proliferation through the activation of the epidermal growth factor receptor (EGFR). A coculture model showed that the contact of antigen-stimulated CD4+ T cells with ASM cells induced high levels of EGFR ligand expression in CD4+ T cells and the activation of matrix metalloproteinase (MMP)-9, required for the shedding of EGFR ligands. The inhibition of EGFR and MMP-9 prevented the increase of ASM cell proliferation after coculture. The hyaluronan receptor CD44 is the dominant mediator of the tight adherence of T cells to ASM and is colocalized with MMP-9 on the cell surface. Moreover, the neutralization of CD44 preventsASM cell hyperplasia. These data provide a novel mechanism by which antigen-stimulated CD4+ T cells induce the remodeling indicative of a direct trophic role for CD4 + T cells. Copyright © 2013 by the American Thoracic Society.