T lymphocytes activated by persistent viral infection differentially modify the expression of metalloproteinases and their endogenous inhibitors, TIMPs, in human astrocytes: Relevance to HTLV-I-induced neurological disease

Activation of T lymphocytes by human pathogens is a key step in the develop ment of immune-mediated neurologic diseases, Because of their ability to in vade the CNS and their increased secretion of proinflammatory cytokines, ac tivated CD4(+) T cells are thought to play a crucial role in pathogenesis, In the present study, we examined the expression of inflammatory mediators the cytokine-induced metalloproteinases (MMP-2, -3, and -9) and their endog enous inhibitors, tissue inhibitors of metalloproteinases (TIMP-1, -2, and -3), in human astrocytes in response to activated T cells, We used a model system of CD4(+) T lymphocytes activated by persistent viral infection (hun an T lymphotropic virus, HTLV-I) in transient contact with human astrocytes , Interaction with T cells resulted in increased production of MMP-3 and ac tive MMP-9 in astrocytes despite increased expression of endogenous inhibit ors, TIMP-1 and TIMP-3. These data suggest perturbation of the MMP/TIMP bal ance, These changes in MMP and TIMP expression were mediated, in part, by s oluble factors (presumably cytokines) secreted by activated T cells. Integr in-mediated cell adhesion is also involved in the change in MMP level, sinc e blockade of integrin subunits (alpha(1), alpha(3), alpha(5), and beta(1)) on T cells resulted in less astrocytic MMP-9-induced expression. Interesti ngly, in CNS tissues from neurological HTLV-I-infected patients; MMP-9 was detected in neural cells within the perivascular space, which is infiltrate d by mononuclear cells. Altogether, these data emphasize the importance of the MMP-TIMP axis in the complex interaction between the CNS and invading i mmune: cells in the context of virally mediated T cell activation.