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

Am J Respir Cell Mol Biol. 2013 Oct;49(4):563-70. doi: 10.1165/rcmb.2012-0356OC.


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 of ASM cell proliferation. We hypothesized that CD4(+) T cells adhere to ASM cells 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 prevents ASM 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Adhesion / immunology
  • Cells, Cultured
  • Coculture Techniques
  • ErbB Receptors / immunology
  • ErbB Receptors / metabolism*
  • Hyaluronan Receptors / immunology
  • Lymphocyte Activation
  • Matrix Metalloproteinase 9 / immunology
  • Matrix Metalloproteinase 9 / metabolism
  • Muscle, Smooth / immunology
  • Muscle, Smooth / metabolism*
  • Myocytes, Smooth Muscle / immunology
  • Myocytes, Smooth Muscle / metabolism*
  • Rats
  • Respiratory System / immunology*
  • Respiratory System / metabolism*


  • Hyaluronan Receptors
  • Egfr protein, rat
  • ErbB Receptors
  • Matrix Metalloproteinase 9