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F. Taheri, J. Stein-Streilein; MMP-9 Expression by ACAID CD8+ T Regulatory Cells Is Required for Suppression. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3722.
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Matrix metalloproteinase 9 (MMP-9) is a gelatinase that degrades components of the extracellular matrix and thus contributes to the invasiveness of tumor cells, tissue infiltration of macrophages and neutrophils, and reepithelialization of damage tissues (wound healing). In addition, MMP-9 also can activate TGFβ. A recent report from our laboratory showed that in vitro induced CD8+ T regulatory (Treg) cells upregulated MMP-9 mRNA more than 20 fold. The purpose of this research was to determine the role of MMP-9 in CD8+ Treg activity.
Induction of ACAID: Antigen was inoculated into the anterior chamber (a.c.) of wild type (WT) or MMP-9 KO mice. A week later experimental mice were deliberately immunized (s.c. injected) with antigen and CFA; the following week the mice were tested for suppression of a delayed hypersensitivity (DH) response post antigen challenge in the ear. Local adoptive transfer assay, LAT assay: In vitro generated CD8+ Treg cells were transferred with sensitized cells and antigen directly into the ear pinnae of the mice. Reconstitution studies: ACAID was induced in CD8+ KO mice that were reconstituted with WT or MMP9-KO spleen cells.
MMP-9 KO mice were unable to develop peripheral tolerance (ACAID) to a.c. inoculated antigen. Moreover, unlike the CD8+ Treg cells from WT mice, the Treg cells generated in vitro from MMP-9 KO spleen cells were unable to suppress Th1 responses (DH). CD8+ T cells from WT, but not from MMP-9 KO mice, were able to reconstitute the ability to induce peripheral tolerance via the eye in otherwise CD8 depleted mice.
These data show that MMP-9 expression is required for CD8+ Treg cell suppressor activity. This is the first report of a role for MMP-9 in Treg activity. MMP-9 could assist in trafficking through tissues but most likely activates TGFβ, a critical cytokine for CD8+ Treg suppression of T effector cell responses.
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