Balancing Thymocyte Adhesion and Motility:A Functional Linkage Between β1 Lntegrinsand The Motility Receptor RHAMM

Abstract

Thymocyte differentiation involves several processes that occur in different anatomic sites within the thymus. Therefore, thymocytes must have the ability to respond to signals received from stromal cells and adopt either adhesive or motile behavior. We will discuss our data indicating human thymocytes use α4β1 integrin, α5β1 integrin and RHAMM to mediate these activities. Immature multinegative (MN; CD3–4–8–19-) thymocytes use α4β1 and α5β1 integrins to mediate weak and strong adhesion. This subset also uses α4β1 integrin to mediate motility. As thymocytes differentiate, they begin to express and use RHAMM to mediate motility in conjunction with α4β1 and α5β1 integrins. Motile thymocytes use β1 integrins to maintain weakly adhesive contacts with substrate to provide traction for locomoting cells, thus weak adhesion is a requirement of motile behavior. Hyaluronan (HA) is also required by thymocytes to mediate motility. HA binding to cell surface RHAMM redistributes intracellular RHAMM to the cell surface where it functions to mediate motility. We propose that the decision to maintain adhesive or motile behavior is based on the balance between low and high avidity binding conformations of β1 integrins on thymocytes and that RHAMM:HA interactions decrease high avidity binding conformations of integrins pushing the balance toward motile behavior.

Hyaluronan Anchored to Activated CD44 on Central Nervous System Vascular Endothelial Cells Promotes Lymphocyte Extravasation in Experimental Autoimmune Encephalomyelitis

“…One candidate HA-binding protein is the receptor for hyaluronan-mediated motility, which is expressed by developing CD3 ϩ thymocytes, and is reported to be largely absent from mature lymphocytes (31)(32)(33). Like CD44, the receptor for hyaluronan-mediated motility can be expressed at the cell surface where it can bind and tether HA and is capable of signaling through Src kinase to influence cytoskeletal rearrangement (34).…”

Signaling Properties of Hyaluronan Receptors

“…These effects are possibly mediated, either directly or indirectly, through integrin receptors. For example, cell surface RHAMM co-regulates migration of thymocytes on fibronectin substrata in concert with the integrin fibronectin receptors, ␣ 4 ␤ 1 or ␣ 5 ␤ 1 (56).…”

Role of Receptor for Hyaluronic Acid-mediated Motility (RHAMM) in Low Molecular Weight Hyaluronan (LMWHA)-mediated Fibrosarcoma Cell Adhesion

“…Role of RHAMM in Fibrosarcoma Cell Adhesion-HA receptor RHAMM has been suggested to mediate HA-induced migration, adhesion, and proliferation in cancer cells (50,51). Therefore, we investigated whether it participates in the HAdependent fibrosarcoma cell adhesion.…”