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Thymus and Immune Cells

Regulation of the Immune System by Laminins

Simon T. and Bromberg J.S.
Trends in Immunology

Laminins are trimeric proteins that are major components of the basement membranes. Each laminin isoform has distinct tissue expression patterns and functions. While laminins have a critical structural role, recent evidence also indicates that they also impact the maturation, migration, and functions of immune cells. Laminins are differentially expressed upon immunity or tolerance and orientate the immune response. This review summarizes the structure of laminins, the modulation of their expression, and their interactions with the immune system. Especially the isoforms 411, 521 and 511 have pleiotropic effects on the immune system. The role of the laminins in autoimmune diseases and transplantation are also discussed.


Laminin-Mediated Interactions in Thymocyte Migration and Development

Savino W., Mendes-da-Cruz D.A., Golbert D.C., Riederer I., Cotta-de-Almeida V.
Front Immunol., 2015

In this review, the authors highlight the role of laminin isoforms for intrathymic T-cell migration and maturation in both physiological and pathological conditions. Intrathymic T-cell differentiation is a key process for the development and maintenance of cell-mediated immunity. Here, the authors propose a multivectorial model for describing intrathymic thymocyte migration. One of the individual vectors comprises interactions mediated by laminins. Several different laminin isoforms are expressed in the thymus, produced mainly by thymic epithelial cells (TECs). Thymocytes and epithelial cells express integrin-type laminin receptors. It has been reported that a mutant mouse that lack laminin-211 exhibits defective thymocyte differentiation. Several data also show haptotactic effects of laminin upon thymocytes and their adhesion on TECs. Interestingly, laminin synergizes with chemokines to enhance thymocyte migration. More recently, the authors show that knocking down the ITGA6 gene (which encodes the α6 integrin chain of laminin receptors) in human TECs modulates a large number of cell migration-related genes and results in changes of adhesion pattern of thymocytes into the thymic epithelium. Overall, laminin-mediated interactions can be placed at the cross-road of the multivectorial process of thymocyte migration, with a direct influence per se, as well as by modulating other molecular interactions associated with the intrathymic-trafficking events.


Laminin-211 controls thymocyte—thymic epithelial cell interactions

Ocampo J.S.P., de Brito J.M,  Corrêa-de-Santana E., Borojevic R., Serra Villa-Verde D.M., Savino W.
Cellular Immunology, 2008

Thymocyte differentiation occurs within the thymic microenvironment. Previous experiments showed that laminin mediates interactions between thymocytes and thymic epithelial cells (TEC) in mice. Here, the authors show constitutive gene expression of various laminin chains in TEC preparations, comprising laminin-111 and laminin-211 isoforms. Immunocytochemistry revealed a selective laminin-211 distribution in the thymic lobules. In vitro, functional assays revealed that laminin-211 enhances TEC/thymocyte adhesion and thymocyte release from thymic nurse cells, as well as the reconstitution of these complexes. Conversely, these interactions are blocked by monoclonal antibodies specific for laminin-211 and the laminin receptor VLA-6. The results show that distinct laminin isoforms in the human thymus are relevant for lymphoepithelial interactions.


Laminin chains in the basement membranes of human thymus

Virtanen I., Lohi J., Tani T., Sariola H., Burgeson R.E., Lehto V-P
Histochemical Journal, 1996

The laminin a2 chain has been suggested to be the only laminin a chain expressed in mouse and human thymus. Here, the authors use monoclonal antibodies to study the expression of laminin chains in samples of fetal and 6-year-old human thymus. The subepithelial basement membrane of the capsule of fetal 16- to 18-week thymus presented a bright immunoreactivity for laminin a1, a3, B1, B3 and g1 chains but not for a2 chain, suggesting the expression of laminin-111 and -332. Most cortical and medullary epithelial cells, including Hassall's corpuscles, however, lacked laminin immunoreactivity. In thymic specimens from 6-year-old children, immunoreactivity for the laminin a1, a3, B1, B3 and g1 chains were invariably found in the subepithelial basement membrane of the capsule and that for laminin a2 chain was now also distinct but more heterogeneous. The present results show that the thymic subepithelial basement membrane of the capsule presents properties that are commonly seen in stratified and combined epithelia, and are compatible with suggestions of the antigenic similarity of thymic epithelial cells and keratinocytes.


Laminins affect T cell trafficking and allograft fate

Warren K.J., Iwami D., Harris D.G, Bromberg J.S., Burrell B.E.
The Journal of Clinical Investigation, 2014

Lymph nodes (LNs) are integral sites for the generation of immune tolerance and migration of CD4+ T cells, and induction of T-regs. Extracellular matrix proteins formed regions within the LN that were permissive for co-localization of alloantigen-presenting cells, alloreactive T cells, and T-regs. Laminin-411 is produced by vascular endothelial and promotes T cell migration. Laminin-511 and laminin-521 are also present in the endothelial basement membrane. However, laminin-511 and fails to promote T cell migration, although T cell co-stimulatory properties have been reported. Here they identified unique expression patterns of laminin proteins that correlated with alloantigen-specific immunity or immune tolerance in mice. Laminin α4 (R&D Systems Inc.) and LN-511 were used for in vitro experiments. The ratio of laminin α4 to laminin α5 was greater in domains within tolerant LNs, compared with immune LNs, and blocking laminin α4 function or inducing laminin α5 overexpression disrupted T cell and dendritic cells localization These data again were commensurate with the in vitro migration results whereby laminin α5 impeded while α4 permitted migration through the endothelium and associated basement membrane. Furthermore, reducing α4 laminin circumvented tolerance induction and induced cardiac allograft inflammation and rejection in murine models. This work identifies laminins as potential targets for immune modulation.


Characterization of a conduit system containing laminin-5 in the human thymus: a potential transport system for small molecules

Drumea-Mirancea M., Wessels J.T., Müller C.A., Essl M., Eble J.A., Tolosa E., Koch M., Reinhardt D.P., Sixt M., Sorokin L., Stierhof Y-D., Schwarz H., Klein G.
Journal of Cell Science, 2006

T cells develop in the thymus in a highly specialized cellular and extracellular microenvironment. Laminin-332 is predominantly found in the medulla of the human thymic lobules. Here, the authors show that laminin-332 is localized in a bi-membranous conduit-like structure, together with matrix components, such as collagen type IV, nidogen, perlecan, fibrillin-1 or -2, tenascin-C or fibrillar collagen types. 3D confocal microscopy suggested a tubular structure, whereas immunoelectron and transmission electron microscopy showed that the core of these tubes contained fibrillar collagens enwrapped by the laminin-332-containing membrane. These medullary conduits are surrounded by thymic epithelial cells, which in vitro were found to bind laminin-332. Dendritic cells were also detected in close vicinity to the conduits.


CCR2+CCR5+ T Cells Producing Matrix Metalloproteinase-9 and Osteopontin in the Pathogenesis of Multiple Sclerosis

Sato W., Tomita A., Ichikawa D., Lin Y., Kishida H., Miyake S., Ogawa M., Okamoto T., Murata M., Kuroiwa Y., Aranami T., Yamamura T.
Journal of Immunology, 2012

To recapitulate the glia limitans layered with parenchymal basal lamina experimentally, we coated the upper sides of Transwell membrane inserts. The upper sides of Transwell membrane inserts (8 mm; Corning) were coated with 10 mg/ml laminin-1 (Sigma) or 20 mg/ml laminin-121. After aspirating the laminin solutions, the membrane inserts were turned upside down, and normal human astrocytes (NHA) were seeded on the lower sides of the membrane inserts. T cells were stimulated, harvested, suspended in the fresh medium, and seeded onto the upper chambers. After 8 h, the cell suspension was collected from the lower chambers after careful pipetting, and absolute numbers of migrated cells were calculated. The T-cell migration across the NHA layered with laminin-111 or -121 was less efficient compared with the migration across the untreated membrane or the membrane treated with laminin alone, thus, this model would exhibit barrier functions against the penetration of activated T cells.