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

Abstract

The thymus supports differentiation of T cell precursors. This process requires relocation of developing thymocytes throughout multiple microenvironments of the organ, mainly with thymic epithelial cells (TEC), which control intrathymic T cell differentiation influencing the formation and maintenance of the immunological synapse. In addition to the proteins of the major histocompatibility complex (MHC), this structure is supported by several adhesion molecules. During the process of thymopoiesis, we previously showed that laminin-mediated interactions are involved in the entrance of T-cell precursors into the thymus, as well as migration of differentiating thymocytes within the organ. Using small interference RNA strategy, we knocked-down the ITGA6 gene (which encodes the CD49f integrin α-chain) in cultured human TEC, generating a decrease in the expression of the corresponding CD49f subunit, in addition to modulation in several other genes related to cell adhesion and migration. Thymocyte adhesion to TEC was significantly impaired, comprising both immature and mature thymocyte subsets. Moreover, we found a modulation of the MHC, with a decrease in membrane expression of HLA-ABC, in contrast with increase in the expression of HLA-DR. Interestingly, the knockdown of the B2M gene (encoding the β-2 microglobulin of the HLA-ABC complex) increased CD49f expression levels, thus unraveling the existence of a cross-talk event in the reciprocal control of CD49f and HLA-ABC. Our data suggest that the expression levels of CD49f may be relevant in the general control of MHC expression by TEC and consequently the corresponding synapse with developing thymocytes mediated by the T-cell receptor.

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

“…Altered Plau expression results in decreased thymic Treg development ( 143 ). Itga6 expression in TECs regulates expression of cell migration and immunologic synapse related genes ( 144 ). Cyr61 expression on TECs boosts progenitor homing ( 145 ), but how the differential interaction with Itgam would impact thymocyte development is less clear.…”

Genomic Regions Associated with Resistance to Gastrointestinal Nematode Parasites in Sheep—A Review

“…This gene was also enriched (p < 0.05) in the gene ontology (GO) term "leukocyte migration" [30]. The levels of expression of the α6-integrin subunit protein produced by the ITGA6 gene have an impact on T-cell adhesion to thymic epithelial cells and impact their migration within the thymus, development, and selection [64]. This integrin has also been implicated in the trafficking of circulating T-cells to the intestinal lamina propria [65].…”

Intrathymic somatotropic circuitry: consequences upon thymus involution

“…The ECM in the thymus is composed of a large variety of molecules, including among others, fibronectins, laminins, and collagens, also acting as a reservoir for soluble factors ( 61 , 62 ). Additionally, integrin-type receptors for these ligands, which are expressed by both developing thymocytes and microenvironmental cells, comprise very late antigen (VLA)-4 (α4β1, CD49d/CD29), VLA-5 (α5β1, CD49e/CD29) and VLA-6 (α6β1, CD49f/CD29) ( 63 , 64 ).…”