Tetraspanin CD9: A Key Regulator of Cell Adhesion in the Immune System

Abstract

The tetraspanin CD9 is expressed by all the major subsets of leukocytes (B cells, CD4⁺ T cells, CD8⁺ T cells, natural killer cells, granulocytes, monocytes and macrophages, and immature and mature dendritic cells) and also at a high level by endothelial cells. As a typical member of the tetraspanin superfamily, a prominent feature of CD9 is its propensity to engage in a multitude of interactions with other tetraspanins as well as with different transmembrane and intracellular proteins within the context of defined membranal domains termed tetraspanin-enriched microdomains (TEMs). Through these associations, CD9 influences many cellular activities in the different subtypes of leukocytes and in endothelial cells, including intracellular signaling, proliferation, activation, survival, migration, invasion, adhesion, and diapedesis. Several excellent reviews have already covered the topic of how tetraspanins, including CD9, regulate these cellular processes in the different cells of the immune system. In this mini-review, however, we will focus particularly on describing and discussing the regulatory effects exerted by CD9 on different adhesion molecules that play pivotal roles in the physiology of leukocytes and endothelial cells, with a particular emphasis in the regulation of adhesion molecules of the integrin and immunoglobulin superfamilies.

Keywords: ADAM17; CD9; ICAM1; activated leukocyte cell adhesion molecule; integrins; lymphocyte function-associated antigen 1; tetraspanins; very late activation antigen 4.

Figure 1

Functional regulation exerted by CD9 on the activity of some immune system adhesion molecules. (A) CD9 regulates ICAM and lymphocyte function-associated antigen 1 (LFA-1) at the immune synapse (IS). Interactions between LFA-1 on the T cell, and its ligand intercellular adhesion molecule 1 (ICAM-1) on the APC surface, take place at the peripheral area of the IS (pSMAC) and are crucial for IS formation and stabilization. The tetraspanin CD9 plays an important role in the IS in two different ways: (1) Through its association with LFA-1 on the T cell, CD9 controls the state of aggregation and adhesive capacity of this integrin. Neoexpression/overexpresion of CD9 reduces the integrin adhesive capacity by generating a larger number of clusters of LFA-1 molecules that individually display a smaller size. (2) On the APC surface CD9 recruits ICAM-1 into TEMs, thus increasing its adhesive capacity. (B) CD9 regulates leukocyte firm adhesion on endothelial cells. The multi-step paradigm of the leukocyte extravasation cascade includes the initial tethering and rolling of the leukocyte on the endothelial surface, followed by the firm adhesion step and transmigration either between two endothelial cells or through the body of an endothelial cell. The firm adhesion step is mediated by the high-affinity interaction of leukocyte integrins LFA-1 (αLβ2) and Mac-1 (αMβ2) with their endothelial counter-receptor ICAM-1, and of integrin VLA-4 (α4β1) with its endothelial ligand VCAM-1. ICAM-1 and VCAM-1 are preorganized in endothelial adhesive platforms (EAPs), through their association with CD9 and CD151 respectively. After leukocyte binding, EAPs evolve into three-dimensional docking structures that emanate from the endothelial surface and embrace the leukocyte. (C) CD9 affects the shedding of leukocyte adhesion molecules mediated by ADAM17. The recruitment of ADAM17 into CD9-organized TEMs (low panel), following the overexpression or neoexpression of this tetraspanin, exerts a negative regulation on the sheddase activity of ADAM17 against different substrates on leukocytic cells, including activated leukocyte cell adhesion molecule (ALCAM). This negative regulation on ADAM17 activity accounts for an increased expression of ALCAM on the cell surface. Additionally, CD9 also induces the aggregation of ALCAM and the concomitant increase in its avidity. Therefore, CD9 augments ALCAM-mediated cell–cell adhesion through this dual mechanism.