Endogenous matrix metalloproteinases 2 and 9 regulate activation of CD4+and CD8+ T cells

Heather L. Benson, Shahriar Mobashery, Mayland Chang, Farrah Kheradmand, Jeong Soo Hong, Gerald N. Smith, Rebecca A. Shilling, David S. Wilkes

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

We reported that inhibiting matrix metalloproteinases (MMP), known to remodel the extracellular matrix, also down-regulated antigen-specific T-cell responses. However, the direct role of MMP2 and MMP9 in regulating intracellular function in T cells is unknown. Markers of cellular activation and cytokine profiles were examined in anti-CD3-stimulated wild-type C57BL/6 mouse-derived CD4+ or CD8+ T cells, or MMP2- or MMP9-deficient (-/-) mice. MMP-sufficient T cells were also treated with SB-3CT, a highly selective inhibitor of MMP2 and MMP9. The effect of MMP-specific inhibition on T cell-dependent, antigen-specific murine lung injury was examined in vivo. SB-3CT induced dose-dependent reductions in anti-CD3-stimulated T-cell proliferation. Although MMP2-/- cells were reduced 20%, anti-CD3-induced proliferation was down-regulated 80-85% in MMP9-/- or in SB-3CT-treated wild-type CD4+ and CD8+ T cells. Intracellular calcium flux was augmented in response toMMP inhibition or deficiency in the same cells, and IL-2 production was reduced in CD4+ and CD8+ MMP9-/- T cells. SB-3CT-mediated MMP2 and MMP9 inhibition abrogated antigen-specific CD8+ T cell-mediated lung injury in vivo. MMPs, particularly MMP9, may function intracellularly to regulate T-cell activation. T cell-targeted MMP inhibition may provide a novel approach of immune regulation in the treatment of T cell-mediated diseases.

Original languageEnglish (US)
Pages (from-to)700-708
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume44
Issue number5
DOIs
StatePublished - May 1 2011

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Keywords

  • Matrix metalloproteinase 2
  • Matrix metalloproteinase 9
  • SB-3CT
  • T cells

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Benson, H. L., Mobashery, S., Chang, M., Kheradmand, F., Hong, J. S., Smith, G. N., Shilling, R. A., & Wilkes, D. S. (2011). Endogenous matrix metalloproteinases 2 and 9 regulate activation of CD4+and CD8+ T cells. American journal of respiratory cell and molecular biology, 44(5), 700-708. https://doi.org/10.1165/rcmb.2010-0125OC