Laminin-Mediated Interactions in Thymocyte Migration and Development

Abstract

Intrathymic T-cell differentiation is a key process for the development and maintenance of cell-mediated immunity, and occurs concomitantly to highly regulated migratory events. We have proposed a multivectorial model for describing intrathymic thymocyte migration. One of the individual vectors comprises interactions mediated by laminins (LMs), a heterotrimeric protein family of the extracellular matrix. Several LMs are expressed in the thymus, being produced by microenvironmental cells, particularly thymic epithelial cells (TECs). Also, thymocytes and epithelial cells express integrin-type LM receptors. Functionally, it has been reported that the dy/dy mutant mouse (lacking the LM isoform 211) exhibits defective thymocyte differentiation. Several data show haptotactic effects of LMs upon thymocytes, as well as their adhesion on TECs; both effects being prevented by anti-LM or anti-LM receptor antibodies. Interestingly, LM synergizes with chemokines to enhance thymocyte migration, whereas classe-3 semaphorins and B ephrins, which exhibit chemorepulsive effects in the thymus, downregulate LM-mediated migratory responses of thymocytes. More recently, we showed that knocking down the ITGA6 gene (which encodes the α6 integrin chain of LM receptors) in human TECs modulates a large number of cell migration-related genes and results in changes of adhesion pattern of thymocytes onto the thymic epithelium. Overall, LM-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.

Cytokine Release and Focal Adhesion Proteins in Normal Thyroid Cells Cultured on the Random Positioning Machine

“…However, it is a fact that laminins interact with several integrin isoforms and are involved in migration and development [35, 68]. Moreover, since the gene expression of LAMA1 was down-regulated in MCS cells, an impact of this gene or protein seems to be very likely.…”

Down-Regulation of Laminin (LN)- α5 is Associated with Preeclampsia and Impairs Trophoblast Cell Viability and Invasiveness Through PI3K Signaling Pathway

“…LNs are composed of three subunits, designated α, β and γ chains, which assemble into a cross-shaped trimer to form 16 different isoforms [6][7][8]. The most widely expressed LN subunit in adult basement membranes is the laminin-α5 chain (LN-α5) [9]. Unique developmental roles of LN-α5 have been studied in knockout (LN5-KO) mice since 1998, the result demonstrated embryos lacking LN-α5 die late in embryogenesis, and exhibit multiple developmental defects, including exencephaly, syndactyly and dysmorphogenesis of placental labyrinth.…”

Small interference ITGA6 gene targeting in the human thymic epithelium differentially regulates the expression of immunological synapse-related genes

“…8,20 In particular, others and we have demonstrated the expression of laminin isoforms in human and murine thymus, as well as the expression of functional laminin receptors by TEC and developing thymocytes, which play a role in the adhesion of thymocytes to TEC in normal murine and human thymuses. 21 CD49f is an ECM cell adhesive protein, a6 integrin chain, encoded by the ITGA6 gene, which can associate with b1 or b4 sub-unities to form laminin receptors. 22 In normal epithelial tissues, a6b4 has been implicated in forming and stabilizing of hemidesmosomes, which contribute to the organization and maintenance of epithelial structure.…”

“…[24][25][26][27] Accordingly, thymocyte adhesion on microenvironmental cells, as well as thymocyte migration, is dependent on laminin-mediated interaction, through integrin-type receptors, such as VLA-6 (a6b1 or CD49f/CD29). 21,28 Recently, we showed that siRNA targeting ITGA6 in TEC could modulate cell migration-related genes, including those coding for ECM as well as chemokine ligands and receptors, promoting a significant decrease in cell adhesion to laminin. 28 In a second vein, the integrin b4 subunit is associated with proliferation of endothelial cells through a molecular association with HLA-ABC, which corresponds to class I molecules of the major histocompatibility complex.…”