Function and Dynamics of Tetraspanins during Antigen Recognition and Immunological Synapse Formation

Abstract

Tetraspanin-enriched microdomains (TEMs) are specialized membrane platforms driven by protein-protein interactions that integrate membrane receptors and adhesion molecules. Tetraspanins participate in antigen recognition and presentation by antigen--presenting cells (APCs) through the organization of pattern-recognition receptors (PRRs) and their downstream-induced signaling, as well as the regulation of MHC-II-peptide trafficking. T lymphocyte activation is triggered upon specific recognition of antigens present on the APC surface during immunological synapse (IS) formation. This dynamic process is characterized by a defined spatial organization involving the compartmentalization of receptors and adhesion molecules in specialized membrane domains that are connected to the underlying cytoskeleton and signaling molecules. Tetraspanins contribute to the spatial organization and maturation of the IS by controlling receptor clustering and local accumulation of adhesion receptors and integrins, their downstream signaling, and linkage to the actin cytoskeleton. This review offers a perspective on the important role of TEMs in the regulation of antigen recognition and presentation and in the dynamics of IS architectural organization.

Keywords: T-cell activation; adhesion receptors; immunological synapse; tetraspanin-enriched microdomains; tetraspanins.

Figure 1

Tetraspanins in the function of APCs. (A) Tetraspanin interactions with pathogen-recognition receptors (PRRs) in APCs. Tetraspanins interact with specific PRRs at the plasma membrane of macrophages and DCs. CD37 associates with dectin-1 and inhibits dectin-1 mediated IL-6 production triggered by the recognition of fungal cell walls. CD9 forms a complex with CD14 and TLR4 and negatively regulates TLR4 signaling in response to LPS. CD81–Rac interaction inhibits TLR2- and IFNAR-signaling pathways and prevents the subsequent activation of STAT1 in response to Listeria monocytogenes. CD36 associates with β1 and β2 integrins and tetraspanins CD9 and CD81 forming a complex that facilitates CD36-signaling and its interaction with FcγRs. Interaction between CD9 and FcγRs promotes phagocytosis and macrophage activation. (B) Tetraspanin interactions during Ag processing and MHC-II biosynthesis. CD63 interacts with dectin-1 in immature DCs and promotes yeast phagocytosis. Both CD63 and CD82 are selectively recruited to yeast-containing phagosomes. CD82 and CD63 are highly enriched in MIIC compartments that contain newly synthesized MHC-II and accessory proteins. (C) Tetraspanin interactions during Ag presentation. Several tetraspanins associate with MHC-I and MHC-II molecules on APCs. Tetraspanins CD9, CD53, CD81, and CD37 associate with MHC-II molecules preferentially at the plasma membrane. MHC-II molecules loaded with a restricted antigenic peptide repertoire are included in TEMs together with accessory molecules and costimulatory molecules. CD9 facilitates MHC-II clustering, and CD151 is involved in the clustering of costimulatory molecules.

Figure 2

Tetraspanins organize the T-cell immunological synapse. Tetraspanin CD81 regulates the organization of the immunological synapse (IS) in CD4⁺ T lymphocytes through the association with CD3ζ at the central SMAC (cSMAC). CD81 controls the localization of the TCR complex and its downstream signaling, positively modulating the phosphorylation of ZAP-70, LAT, and ERK1/2 (dashed line). At the peripheral area of the cell–cell contact (pSMAC), tetraspanins CD9, and CD151 are important for integrin VLA-4 relocalization and activation, positively regulating the integrin downstream phosphorylation of FAK and ERK1/2 (lines with small dashes). At this location, CD81 also interacts with the adhesion receptor ICAM-1, regulating its segregation during IS maturation. Tetraspanin CD82 accumulates at the pSMAC and triggers actin polymerization and the activation of the Rho GTPase pathway (RhoA, Rac1, and Cdc42). The activation of this pathway induces the phosphorylation and the association of Vav1 and SLP76 (dotted lines), potentiating the phosphorylation of the TCR signaling molecules LAT and ZAP-70. In APCs, CD81 is enriched at the IS and several tetraspanins are described to associate with MHC-II. Moreover, CD151, CD37, and Tssc6 were described to regulate antigen presentation by DCs.