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

Abstract

Activation of T lymphocytes by human pathogens is a key step in the development of immune-mediated neurologic diseases. Because of their ability to invade the CNS and their increased secretion of proinflammatory cytokines, activated 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 endogenous 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 (human T lymphotropic virus, HTLV-I) in transient contact with human astrocytes. Interaction with T cells resulted in increased production of MMP-3 and active MMP-9 in astrocytes despite increased expression of endogenous inhibitors, TIMP-1 and TIMP-3. These data suggest perturbation of the MMP/TIMP balance. These changes in MMP and TIMP expression were mediated, in part, by soluble factors (presumably cytokines) secreted by activated T cells. Integrin-mediated cell adhesion is also involved in the change in MMP level, since blockade of integrin subunits (α1, α3, α5, and β1) on T cells resulted in less astrocytic MMP-9-induced expression. Interestingly, in CNS tissues from neurological HTLV-I-infected patients, MMP-9 was detected in neural cells within the perivascular space, which is infiltrated by mononuclear cells. Altogether, these data emphasize the importance of the MMP-TIMP axis in the complex interaction between the CNS and invading immune cells in the context of virally mediated T cell activation.

Morbillivirus Infection of the Mouse Central Nervous System Induces Region-Specific Upregulation of MMPs and TIMPs Correlated to Inflammatory Cytokine Expression

“…An MMP/ TIMP imbalance may also be involved in the virally induced neural damage seen in patients suffering from viral meningitis or human immunodeficiency virus (HIV)-associated encephalitis (13,34) and in patients suffering from tropical spastic paraparesis/human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (TSP/HAM) (20,23). Indeed, our previous work has shown that MMP-9 and TIMP-3 are preferentially upregulated in the cerebrospinal fluid (CSF) and parenchyma of TSP/HAM patients compared to that in asymptomatic virus carriers (35), these data being consistent with the upregulation of MMP-3, MMP-9, TIMP-1, and TIMP-3 expression seen in neural cells following contact with HTLV-1-infected T lymphocytes (21,22).…”

Semaphorin CD100 from Activated T Lymphocytes Induces Process Extension Collapse in Oligodendrocytes and Death of Immature Neural Cells

“…7G) of spinal cord from patient with high inflammation level (case 1). Interestingly, we had detected the matrix metalloproteinase-9 within astrocytosis in the spinal cord of this patient (35). In contrast, the few CD45RO-positive cells present in spinal cords of nonneuroinflammatory patients were all CD100 negative (two cases studied; data not shown).…”

“…Oligodendrocytes were identified in the rat primary glial culture by immunofluorescence on culture slide or by flow cytometry (5,35), with antiCNPase (Sigma-Aldrich, St. Louis, MO), anti-GalCer, anti-NG2 (Chemicon International, Temecula, CA), anti-myelin-associated glycoprotein (Boehringer Mannheim, Indianapolis, IN), and anti-myelin basic protein (Serotec, Oxford, U.K.) mAbs. Astrocytes were identified in the same conditions with a rabbit polyclonal Ab (anti-GFAP; DAKO, Carpenteria, CA).…”

“…These T lymphocytes were transiently cocultured, as previously described (35), with the following human and rat neural cells (ratio 1/10, respectively) growing on culture slide or in flask: 1) the human pluripotent neural precursor cell line Dev, which has the ability to differentiate into neurons, astrocytes, and oligodendrocytes (36,37); 2) primary culture of rat glial cells (38), which contained 35-54% oligodendrocytes, the remaining cells corresponding to glial acidic fibrillary protein (GFAP)-positive astrocytes. The oligodendrocytes have distinct phenotypic stages identified with a panel of specific Abs by immunochemistry or flow cytometry (see below): early oligodendrocyte precursor (pre-oligodendrocyte) expressing the NG2 chondroitin sulfate (10 -15%), immature oligodendrocyte expressing galactocerebroside (GalCer, 17-25%) and cyclic nucleotide phosphodiesterase (CNPase), mature oligodendrocyte expressing myelin-associated glycoprotein (3-15%) and myelin basic protein, and 3) human fetal neural cells cultivated from the subventricular zone identified by immunodetection of ␤3-tubulin.…”

Immunohistochemical analysis of MMP-9, MMP-2 and TIMP-1, TIMP-2 expression in the central nervous system following infection with viral and bacterial meningitis.

“…These findings may indicate that MMP-TIMP complexes form during inflammation. Astrocytes are an important source of TIMP activity [15,16], and a net balance between MMPs and TIMPs may be involved in the pathogenesis of CNS disease [17]. In addition to inhibiting MMPs, TIMPs are multifunctional molecules that have distinct biological roles [18].…”