A role for MMP‐9 in CD8⁺ T regulatory suppressor function

Abstract

Matrix metalloproteinase 9 (MMP‐9) belongs to a family of enzymes known for their ability to degrade extracellular matrix components. Macrophages, neutrophils and epithelial cells express MMP‐9 and use MMP‐9 to travel through tissues. However, MMP‐9 has other biological functions such as activating TGFβ. A recent report from our laboratory showed that CD8+ T regulatory cells upregulated MMP‐9 mRNA during the induction of peripheral tolerance through the eye. To test the postulate that MMP‐9 has a role in CD8+ Treg activity, we examined MMP‐9 KO mice and determined that they were unable to develop peripheral tolerance to anterior chamber inoculated antigen. Because MMP‐9 could be involved in trafficking to the site of antigen as well as suppression of T cell effector function, we adoptively transferred in vitro generated Treg cells directly into the ears of mice challenged with immune cells and antigen. Unlike the CD8+ Treg cells from wild type mice, the Treg cells generated with MMP‐9 KO were unable to suppress Th1 responses (delayed hypersensitivity). Our findings indicate that CD8+ Treg cells must express MMP‐9 for optimal suppressor activity. Since MMP‐9 also has the ability to activate TGF, the possibility is raised that CD8+ Treg derived MMP‐9 contributes to the activation of latent TGFβ in the CD8+ Treg cell which in turn contributes to the suppression of the Th1 response. Supported by NIH: EY 016476.