injection of CD3ε antibody mimicking negative selection 34. Odaka and colleagues (2005) reported a transient increase in the expression of MMP-9 in thymic tissue of Balb/c mice 16–24 hours after a single i.p. The reasons behind these discrepancies remain to be experimentally addressed.
However, a later study has revealed a dramatic decrease in the proliferation of MMP-9 knockout T cells as well as in IL-2 and CD25 production in response to stimulation with anti-CD3 antibody 23. In agreement with this conclusion, addition of recombinant MMP-9 to effector T cells stimulated with CD3/CD28-coated beads strongly suppressed their proliferation 21. These data appear to suggest that MMP-9 activity suppresses T cell activation regardless of cell type of origin. Intriguingly, the authors also observed increased proliferation of wild-type T cells derived from mice stimulated by MMP-9-deficient dendritic cells in mixed lymphocyte reaction, as compared to stimulation with wild-type DC.
Using mixed lymphocyte reaction assays, two studies from the same group reported an increased proliferation of MMP-9-deficient T cells upon stimulation with Balb/c dendritic cells, and increased production of IL-12 and IFNγ 32, 33. In addition, purity analysis of MMP-9-producing cell populations has not been fully reported in multiple studies.ĭirect attempts to evaluate the involvement of MMP-9 into T cell activation by comparing MMP-9-sufficient and -deficient peripheral T cell responses have yielded conflicting data. Finally, both human and mouse T cells and T cell lines have been shown to express and secrete active MMP-9 in response to antigenic stimulation 22, 23, 24, upon chemical stimulation 25, 26, 27, 28, in response to tumors 29, and downstream of cell adhesion-related signals 30, 31, although the regulation and biological significance of T cell intrinsic production of MMP-9 remain poorly understood. Chemical inhibition of MMP-9 reduces proliferation of regulatory T cells in the presence of CD3/CD28-coated microbeads in vitro, although puzzlingly so does the addition of recombinant MMP-9 in the same study 21. Another possible role for MMP-9 arises from the observation that MMP-9 produced by cancer cells cleaves CD25 expressed on the surface of tumor-infiltrating T cells and reduces their proliferation in vitro 20, suggesting that a similar mechanism may downregulate T cell activation in vivo by limiting T cell reactivity to IL-2. Indeed, MMP-9 deficiency results in reduced recruitment of T cells and macrophages and attenuated pathology in experimental glomerulonephritis 5. It is likely that the same mechanism may also provide immunosuppressive input in both conventional and regulatory T cell-mediated responses since LFA-1 interaction with ICAM-1 is crucial for immune synapse stabilization and T cell activation 19. Cleavage of ICAM-1 by MMP-9 protects cultured breast cancer cells from NK cell-mediated cytotoxicity 18. A growing body of evidence also indicates that MMP-9 may play a more direct role in the regulation of T cell activation, although the data remain highly fragmented. MMP-9-deficient mice display elevated levels of autoantibodies to a variety of antigens 17. MMP-9-mediated cleavage has also been shown to regulate the activity of a number of cytokines and chemokines 11, 12, 13, 14, 15, 16.
It has been well documented that processing of extracellular matrix by MMP-9 is crucial for movement through and invasion into tissues by multiple cell types, including cancer cells, neutrophils, macrophages, dendritic and T cells 3, 4, 5, 6, 7, 8, 9, 10. Gelatinase B/matrix metalloproteinase-9 (MMP-9) is a calcium-dependent, zinc-containing endopeptidase involved into the remodeling of extracellular matrix in a wide variety of biological phenomena, and an increasing body of evidence suggests that it plays an important role in the regulation of multiple immune processes 1, 2.
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