Tetraspanin microdomains in immune cell signalling and malignant disease

Abstract

A contemporary goal of researchers in leucocyte signalling has been to uncover how cells physically organize and compartmentalize signalling molecules into efficient, regulated signalling networks. This work has revealed important roles of membrane microdomains that are characterized by their distinctive protein and lipid compositions. Recent studies have demonstrated that besides typical cholesterol- and glycosphingolipid-enriched 'rafts', leucocyte membranes are equipped with a different type of microdomain, made up of tetraspanin proteins. Tetraspanin proteins are involved in the organization of tetraspanin-enriched microdomains by virtue of their capacity to specifically associate with key molecules, including integrins, leucocyte receptors and signalling proteins. The aspects of leucocyte function influenced by tetraspanin microdomains include adhesion, proliferation and antigen presentation. However, the mechanisms by which tetraspanin complexes link to intracellular signalling pathways, are still largely unknown. This review discusses how tetraspanin microdomains might function to regulate signalling in lymphoid and myeloid cells, and how they relate to lipid rafts. In addition, we discuss new insights into the role of tetraspanins in malignant disease.

Regulation of NK cell trafficking by CD81

“…In this context tetraspanins are an especially interesting group of molecules. These molecules represent a large family of evolutionary conserved cell-surface proteins that are expressed on a wide range of human cells among them all cells of the immune system [12]. Tetraspanins are organized in a cell-surface network containing several different tetraspanins that interact specifically with each other and their associated proteins, called the tetraspanin web.…”

Tetraspanin CD37 contributes to the initiation of cellular immunity by promoting dendritic cell migration

“…The cellular processes regulated by tetraspanin-mediated molecular organization include proliferation, adhesion and migration [2,3]. In immune cells, many important cell surface molecules, such as integrins, co-receptors, pattern recognition receptors and MHC molecules, are incorporated into tetraspanin-enriched microdomains [4][5][6].CD37 has recently attracted interest as a target for monoclonal antibodies with therapeutic potential in B-cell malignancies [7,8]. However, most of what is known about the contribution of CD37 to immunology has been gleaned from CD37…”

Simulations of the NK Cell Immune Synapse Reveal that Activation Thresholds Can Be Established by Inhibitory Receptors Acting Locally

“…Activating signals lead to directed movement of molecules (14,18,19), and of several types of membrane microdomains (20)(21)(22)(23)(24)(25)(26)(27)(28)(29), toward the center of the contact area. LFA-1 molecules segregate into a ring surrounding the center of the contact area, due to the inward movement of membrane microdomains, with which nonactivated LFA-1 molecules do not associate, and possibly also due to membrane stress caused between the short bonds of NK cell receptors and ligands and the longer LFA-1-ICAM-1 bonds (30).…”