Orchestration of Immunological Synapse Assembly by Vesicular Trafficking

Abstract

Ligation of the T-cell antigen receptor (TCR) by cognate peptide bound to the Major Histocompatibility Complex on the surface of an antigen-presenting cell (APC) leads to the spatial reorganization of the TCR and accessory receptors to form a specialized area of intimate contact between T cell and APC, known as the immunological synapse (IS), where signals are deciphered, coordinated, and integrated to promote T cell activation. With the discovery that an endosomal TCR pool contributes to IS assembly and function by undergoing polarized recycling to the IS, recent years have witnessed a shift from a plasma membrane-centric view of the IS to the vesicular trafficking events that occur at this location following the TCR-dependent translocation of the centrosome toward the synaptic membrane. Here we will summarize our current understanding of the trafficking pathways that are responsible for the steady delivery of endosomal TCRs, kinases, and adapters to the IS to sustain signaling, as well as of the endocytic pathways responsible for signal termination. We will also discuss recent evidence highlighting a role for endosomes in sustaining TCR signaling after its internalization at the IS and identifying the IS as a site of formation and release of extracellular vesicles that allow for transcellular communication with the APC.

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

“…Fluorescent light microscopy provides the unique advantage of being able to observe live cells, illuminating IS dynamics such as the spatial arrangement of receptors and ligands over time. Work in this area has been pioneered by the study of the T cell IS, which has been extensively reviewed elsewhere (7,9,76,(114)(115)(116)(117)(118)(119). Study of the T cell IS has been in part driven by a more reductionist approach to parse the very complex IS into more digestible pieces.…”

“…This is the point where activating receptors on the NK cell surface bind to the Fc domain of antigen-engaged antibodies and initialize a cascade of events that lead to NK cell activation and ultimately target-cell death. Extensive studies of the T cell receptor have provided valuable insight into the organization of the T cell IS ( 7 – 10 ), but much less is known about the NK cell immune synapse (NKIS).…”

Effect of Pharmacological Inhibition of the Catalytic Activity of Phosphatases of Regenerating Liver in Early T Cell Receptor Signaling Dynamics and IL-2 Production

“…The traffic of PRL-1 and PRL-3 to the endosomal compartment and the IS suggests that these enzymes might regulate the secretion of cytokines, in particular those secreted to the IS, such as interleukin-2 (IL-2) [21]. Nevertheless, PRLs might also regulate the delivery to the IS of intracellular pools of the TCR or signaling molecules Lck and LAT, which also travel to the IS in the endosomal compartment [17,22].…”

A CVID-associated variant in the ciliogenesis protein CCDC28B disrupts immune synapse assembly

“…Polarized recycling from an intracellular endosome-associated pool is a key mechanism exploited by T cells to replenish the IS with TCRs as exhausted receptors are internalized, which allows for sustained signaling during the extended timeframe required for T-cell activation 13,14 . The trafficking machinery responsible for TCR internalization at the plasma membrane, sorting at EEs, and recycling to the cell surface has been delineated in recent years 14 . Here we identify CCDC28B as a new player in the TCR trafficking pathway that acts at EEs, where it couples FAM21 and its binding partner WASH to retromer to promote local actin polymerization (Fig.S6D).…”