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.
Highlights
Reviewed by: Tomasz Zal, University of Texas MD Anderson Cancer Center, USA Alessandra Cambi, Radboud University Medical Centre, Netherlands
Tetraspanin CD81 accumulates at the immunological synapse (IS) in both T lymphocytes and antigenpresenting cells (APCs) [125] (Figure 2), and we recently found that CD81 is an important molecular organizer of the IS structure at the T cell side [81]
The conformational changes of β integrin extracellular domains can be controlled by the actin linker protein talin [134], which accumulates at the peripheral SMAC (pSMAC) [91] and is required for lymphocyte function-associated antigen 1 (LFA-1) activation mediated by the T-cell receptor (TCR) [135]
Summary
The plasma membrane of antigen-presenting cells (APCs) contains specialized membrane microdomains that organize the spatial distribution of MHC and associated proteins, pattern-recognition receptors (PRRs), and integrins, which are essential for efficient Ag recognition, presentation, and the activation of the T cell. 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. Using the Listeria monocytogenes infection model, we recently demonstrated that CD81 is able to interfere with TLR2- and interferon-α/β receptor (IFNAR)-mediated bacterial recognition in DCs, modulating the subsequent CD8+ T cell response [53] (Figure 1A; Table 1). In human monocytes and skin-derived DCs, CD9 and CD81 are molecular partners of the trimeric form of FcεRI (Figure 1; Table 1), the high-affinity receptor for IgE, and are overexpressed in patients with atopic dermatitis [49]
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