The Regulatory Role Of Matrix Metalloproteinases In T Cell Activation

dc.contributor.advisorWilkes, David S.
dc.contributor.authorBenson, Heather Lynette
dc.date2009en
dc.date.accessioned2009-12-08T19:00:31Z
dc.date.available2009-12-08T19:00:31Z
dc.date.issued2009-10
dc.degree.disciplineDepartment of Biochemistry & Molecular Biologyen
dc.degree.grantorIndiana Universityen
dc.degree.levelPh.D.en
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en
dc.description.abstractIntroduction: Matrix metalloproteinases (MMPs) are known for their role in extracellular matrix remodeling, but their role in regulating intracellular immune cell function is unknown. We reported that MMP inhibition down regulated T cell proliferation in response to alloantigens and autoantigens; but the direct role of MMP involvement in T cell activation has not been reported. Methods: MMP deficient or MMP sufficient wild-type CD4+ or CD8+ T cells from C57BL/6 mice were treated with SB-3CT, a specific inhibitor of MMP2 and MMP9, stimulated with anti-CD3 Ab, alone, or with IL-2 or CD28. Cellular activation and cytokine profiles were examined. A mouse model of antigen specific T cell mediated lung injury was used to examine MMP inhibition in antigen-specific T cell mediated lung injury. Results: SB-3CT (1-25μM) induced dose-dependent reductions in anti-CD3 Ab-induced proliferation (p<0.0001). Compared to wild-type, MMP9-/- CD4+ and CD8+ T cells proliferated 80-85% less (p<0.001) in response to anti-CD3 Ab. Compared to untreated or wild-type cells, anti-CD3 Ab-induced calcium flux was enhanced in SB-3CT-treated or MMP9-/- CD4+ and CD8+ T cells. Cytokine transcripts for IL-2, TNF-α and IFN-γ were reduced in both CD4+ and CD8+ MMP9-/- T cells, as well as in SB3CT treated CD4+ T cells. MMP inhibition dampened antigen-specific T cell mediated lung injury. Conclusions: Although known to be functional extracellularly, the current data suggest that MMPs function inside the cell to regulate intracellular signaling events involved in T cell activation. T cell targeted MMP inhibition may provide a novel approach of immune regulation in the treatment of T cell-mediated diseases. - David S. Wilkes, M.D., Chair.en
dc.identifier.urihttps://hdl.handle.net/1805/2019
dc.identifier.urihttp://dx.doi.org/10.7912/C2/1849
dc.language.isoen_USen
dc.subjectT cell activationen
dc.subjectMMP9en
dc.subjectMatrix Metalloproteinasesen
dc.subject.lcshMetalloproteinasesen
dc.subject.lcshT cellsen
dc.titleThe Regulatory Role Of Matrix Metalloproteinases In T Cell Activationen
dc.typeThesisen
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