Endogenous Matrix Metalloproteinases 2 and 9 Regulate Activation of CD4+ and CD8+ T cells

HL Benson, S Mobashery, M Chang… - American journal of …, 2011 - atsjournals.org
HL Benson, S Mobashery, M Chang, F Kheradmand, JS Hong, GN Smith, RA Shilling…
American journal of respiratory cell and molecular biology, 2011atsjournals.org
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 …
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 to MMP 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.
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