Antigen-specific CD4+ T cells drive airway smooth muscle remodeling in experimental asthma
David Ramos-Barbón, … , Elizabeth D. Fixman, James G. Martin
David Ramos-Barbón, … , Elizabeth D. Fixman, James G. Martin
Published June 1, 2005
Citation Information: J Clin Invest. 2005;115(6):1580-1589. https://doi.org/10.1172/JCI19711.
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Research Article Pulmonology

Antigen-specific CD4+ T cells drive airway smooth muscle remodeling in experimental asthma

Abstract

Airway smooth muscle (ASM) growth contributes to the mechanism of airway hyperresponsiveness in asthma. Here we demonstrate that CD4+ T cells, central to chronic airway inflammation, drive ASM remodeling in experimental asthma. Adoptive transfer of CD4+ T cells from sensitized rats induced an increase in proliferation and inhibition of apoptosis of airway myocytes in naive recipients upon repeated antigen challenge, which resulted in an increase in ASM mass. Genetically modified CD4+ T cells expressing enhanced GFP (EGFP) were localized by confocal microscopy in juxtaposition to ASM cells, which suggests that CD4+ T cells may modulate ASM cell function through direct cell-cell interaction in vivo. Coculture of antigen-stimulated CD4+ T cells with cell cycle–arrested ASM cells induced myocyte proliferation, dependent on T cell activation and direct T cell–myocyte contact. Reciprocally, direct cell contact prevented postactivation T cell apoptosis, which suggests receptor-mediated T cell–myocyte crosstalk. Overall, our data demonstrate that activated CD4+ T cells drive ASM remodeling in experimental asthma and suggest that a direct cell-cell interaction participates in CD4+ T cell regulation of myocyte turnover and induction of remodeling.

Authors

David Ramos-Barbón, John F. Presley, Qutayba A. Hamid, Elizabeth D. Fixman, James G. Martin

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Inhibition of CD4+ T cell apoptosis by direct T cell–ASM cell contact in...
Inhibition of CD4+ T cell apoptosis by direct T cell–ASM cell contact indicates bidirectional crosstalk. Purified OVA-stimulated CD4+ T cells were cocultured for 48 hours with ASM cells either separated in Transwells or in direct contact. Additionally, CD4+ T cells were cocultured in contact with the ASM cells without prior stimulation in vitro. The cocultures were exposed to BrdU for 24 hours and the CD4+ T cells analyzed for BrdU incorporation and total cell DNA content. (A) BrdU versus DNA density plots shown with the corresponding DNA histograms. T cell BrdU incorporation plotted against DNA content defines the following regions: 1, live quiescent cells (absence of BrdU incorporation and in G0/G1 phase of the cell cycle); 2, cells undergoing proliferation (incorporation of BrdU and in S or G2/M phases of the cell cycle); 3, live postmitotic cells (incorporation of BrdU and again in G0/G1 phase of the cell cycle); 4, postactivation apoptotic cells (incorporation of BrdU and subdiploid DNA content); and 5, apoptotic quiescent cells (no BrdU incorporation and subdiploid DNA content). “A” in the DNA histograms corresponds to the subdiploid or sub-G0/G1 region and represents both quiescent and postactivation apoptotic T cells. M, cells in mitosis. (B) The corresponding side (SSC-H) versus forward (FSC-H) scatter dot plots are multicolor gated in the BrdU/DNA density plot regions defined in A. (C) Quantitative analysis of the cytometric regions defined in A and B. Data are from 4 independent experiments. *P < 0.05. Apop, apoptotic cells; incorp, incorporation.