MMP19 Is Essential for T Cell Development and T Cell-Mediated Cutaneous Immune Responses

Abstract

Matrix metalloproteinase-19 (MMP19) affects cell proliferation, adhesion, and migration in vitro but its physiological role in vivo is poorly understood. To determine the function of MMP19, we generated mice deficient for MMP19 by disrupting the catalytic domain of mmp19 gene. Although MMP19-deficient mice do not show overt developmental and morphological abnormalities they display a distinct physiological phenotype. In a model of contact hypersensitivity (CHS) MMP19-deficient mice showed impaired T cell-mediated immune reaction that was characterized by limited influx of inflammatory cells, low proliferation of keratinocytes, and reduced number of activated CD8+ T cells in draining lymph nodes. In the inflamed tissue, the low number of CD8+ T cells in MMP19-deficient mice correlated with low amounts of proinflammatory cytokines, especially lymphotactin and interferon-inducible T cell α chemoattractant (I-TAC). Further analyses showed that T cell populations in the blood of immature, unsensitized mice were diminished and that this alteration originated from an altered maturation of thymocytes. In the thymus, thymocytes exhibited low proliferation rates and the number of CD4+CD8+ double-positive cells was remarkably augmented. Based on the phenotype of MMP19-deficient mice we propose that MMP19 is an important factor in cutaneous immune responses and influences the development of T cells.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…In this respect, consistent evidences highlight a role in the modulation of cell motility even under physiological conditions: degradation of laminin is associated to promotion of epithelial cells as well as keratinocytes migration and proliferation (Sadowski et al, 2003(Sadowski et al, , 2005. Myeloid cells and T-lymphocytes efficiently compartmentalize the enzyme at their leading edge through interaction with unknown cell surface molecules, to improving extravasation and migration toward the flogistic site (Beck et al, 2008;Mauch et al, 2002). Additional evidence of a positive influence of MMP-19 in tumor growth come from studies in vitro on breast cancer cells where siRNA-mediated inhibition of the enzyme down-regulates tumor invasiveness (Hegedüs et al, 2008).…”

Metalloproteinases promote plaque rupture and myocardial infarction: A persuasive concept waiting for clinical translation

“…1), there appear to be no studies relating MMP-19 knockout to levels of atherosclerosis. MMP-19 null mice are viable and fertile but have greatly reduced immune inflammatory responses in the skin [78] and increased allergic reactions in the lungs [79], suggesting opposite roles in Thelper1 and Thelper2 dominated responses. These changes might be expected to translate to increased atherosclerosis.…”

Matrix Metalloproteinase-19 Promotes Metastatic BehaviorIn Vitroand Is Associated with Increased Mortality in Non–Small Cell Lung Cancer

“…Gene expression for MMP19 was determined using Taqman (Applied Biosystems, Foster City, CA) (16,17). Full details are presented in the METHODS section of the online supplement.…”