Gelatinases (MMP-2 and MMP-9) are preferentially expressed by Th1 vs. Th2 cells

https://doi.org/10.1016/j.jneuroim.2005.02.001Get rights and content

Abstract

T helper subsets, Th1 and Th2, which are associated with different types of immune reactions, are distinguished by their cytokines' profiles and expression of different chemokine receptors, that may differentially influence their migratory capacity. The present study examined the expression of matrix metalloproteinases, (MMP)-2 and MMP-9, by the two CD4+ Th cell subsets and the role of these proteases in their migration. We observed that migration of CD4+ T cells is dependent on the gelatinases, and that the migratory capacity of Th1 is higher than Th2 cells. In addition, Th1 in comparison to Th2 cells, from both human (healthy subjects and multiple sclerosis (MS) patients) as well as from murine origin, secrete higher levels of MMP-2 and MMP-9. These novel findings contribute to the understanding of the physiological Th1 and Th2 immune responses as well as the enhanced Th1 reactivity in immune-mediated diseases, such as MS, in which enhanced levels of MMP-2 and MMP-9 are associated with disease processes.

Introduction

Migration of T cells to target tissues is of vital importance to physiological immune surveillance as well as their response to pathogens. The T cell transmigration from the blood stream involves transient adhesion to the vascular endothelium and focal degradation of the supporting vascular basement membrane (BM) and surrounding extracellular matrix (ECM). The matrix metalloproteinases (MMPs), a family of proteolytic enzymes, secreted by a variety of cells, amongst them T cells, play a central role in the extravasation process (Goetzl et al., 1996). In particular, the gelatinase subfamily, comprising MMP-2 and MMP-9, which degrades collagen type IV, laminin, fibronectin and gelatin, is key a participant in this process (Goetzl et al., 1996, Yong et al., 1998). However, unrestrained expression of MMPs has been suggested to contribute to aberrant immune cells infiltration into tissue and possible target tissue destruction, characteristic of autoimmune processes. In addition, different studies have provided supporting evidence of the specific involvement of MMP-2 and MMP-9 in blood brain barrier (BBB) eruption, enabling the influx of monocytes and T cells into the central nervous system (CNS) in disorders such as multiple sclerosis (MS) and its animal disease model, experimental autoimmune encephalomyelitis (EAE) (Kieseier et al., 1998, Galboiz et al., 2001, Lindberg et al., 2001, Mandler et al., 2001, Bar-Or et al., 2003).

MS, a chronic demyelinating disease of the CNS, is considered to be mediated by T helper (Th)1 cells, while Th2 cells seem to have protective and repair-promoting functions in this disease. Accordingly, elevated levels of Th1 cells are found in brain, blood and CSF of MS patients (Balashov et al., 1999). The Th1 and Th2 subsets are distinguished by their characteristic production of divergent cytokine profiles (Mosmann et al., 1986) and by their involvement in different types of immune reactions. Th1 cells secrete IFN-γ, IL-2, TNF-α and lymphotoxin, and participate in cell-mediated responses to intracellular pathogens. On the other hand, Th2 cells produce IL-4, IL-5, IL-10 and IL-13 and are associated with humoral immune responses against extracellular pathogens; (Sher and Coffman, 1992, Abbas et al., 1996). Previous studies conducted by various groups including ours, demonstrated up-regulation of MMP-9 by Th1 related cytokines, while Th-2 cytokines, such as IL-4 and IL-10, were found to down-regulate MMP-9 expression (Lacraz et al., 1992, Quiding-Jarbrink et al., 2001, Abraham et al., 2002). Th1 and Th2 are also distinguished by their expression of different chemokine receptors. The chemokine receptors CCR5 and CXCR3 are predominantly expressed by Th1 cells, while CCR4 are preferentially expressed by Th2 cells (Bonecchi et al., 1998, Sallusto et al., 1998). This differential expression of chemokine receptors may lead to the recently reported differences in the migratory behavior of CD4+ Th1 and Th2 subsets (Katakai et al., 2002, Song et al., 2003). These differences may play a role in the initiation and regulation of Th1 and Th2 immune responses, physiologic inflammatory processes, as well as T cell-mediated immunopathology. In the present study, we investigated the expression of gelatinases by Th1 and Th2 cells. Since Th1 and Th2 cells drive different types of immune responses, we hypothesized that the differential expression of chemokines' receptors would affect the migration pattern or activity of Th1 cells in comparison to that of Th2 cells, and that these distinct T cell immune phenotypes may express differentiating patterns of MMPs such as gelatinases.

Section snippets

Subjects

Patients (n=8) with definite MS according to the Poser criteria (Poser et al., 1983), followed at the Partners Multiple Sclerosis Center of Brigham and Women's and Massachusetts General Hospitals, were included in the study. All patients were untreated and were diagnosed as relapsing remitting in a clinically stable phase of the disease. Their average age was 36.4±9.3 years, disease-related disability according to the expanded disability status scale (EDSS) (Kurtzke, 1983) ranged between 0 and

Migration of T cells induced by chemokines is mediated by MMPs

A transwell system in which different chemokines were added as stimulants was employed to investigate the migration of T cells (Fig. 2). The chemokines added were: RANTES, a ligand of CCR5; IP-10, a ligand of CXCR3 (Th1 specific) and TARC a ligand of CCR4 (Th2 specific). The number of T cells that had migrated to the lower chamber was counted and results demonstrated that these stimulants induced migration of CD4+ T cells, while the number of migrating T cells was highest in the presence of

Discussion

The present study examined the production of the gelatinases, MMP-2 and MMP-9, by Th1 and Th2 cells and the role of these MMPs in the migratory activity of these T cell subsets. Our study indicated that the migration of CD4+ T cells is dependent on MMPs activity, and that the migratory capacity of Th1 cells is higher than Th2 cells and more involves MMP-2 and MMP-9. A distinct difference was found in the levels of secreted gelatinases by Th1 vs. Th2 cells, both of human as well as murine

Acknowledgements

This work was supported by funds provided by the Rappaport Institute for Research in the Medical Sciences and the Technion-Israel Institute of Technology, Haifa, Israel. We thank V.K. Kuchroo for kindly providing the mouse cell lines.

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