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.
Highlights
The differentiation of naïve T cells into armed effectors able to promote the elimination of pathogens or to kill cancer cells is initiated by signals triggered by the T-cell receptor (TCR) following engagement by specific peptide antigen associated to the Major Histocompatibility Complex on antigen-presenting cells (APC)
While the immunological synapse (IS) has long been considered from a plasma membrane-centric viewpoint, endocytic traffic has emerged as a central determinant in sustaining signaling at the IS over the extended timeframe required for T cell activation (Finetti et al, 2015a, 2017; Onnis et al, 2016)
Recent developments have highlighted new roles for endocytic traffic in IS signaling both inside the cell, where internalized T-cell antigen receptor (TCR) sustain signaling from an endosomal localization, and at the IS membrane, wherefrom miRNA-enriched exosomes and TCR-enriched ectosomes are released for transcellular communication with the cognate APC (Mittelbrunn et al, 2011; Choudhuri et al, 2014)
Summary
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. 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.
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