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Signaling at the immune synapse: vesicular trafficking takes the stage

Cellular & Molecular Immunology volume 10, pages 459–462 (2013)Cite this article

In this issue of Nature Immunology, Larghi and colleagues1 report the involvement of the SNARE (soluble N-ethylmaleimide-sensitive protein-attachment protein receptor) vesicle-associated membrane protein 7 (VAMP7), which regulates vesicular trafficking to the neurological synapse, in signaling downstream of the T-cell antigen receptor (TCR) and T-cell activation. Namely, they demonstrate that VAMP7 promotes the recruitment to TCR activation sites of the intracellular vesicular pool of the LAT (linker for activation of T cells) adaptor, thereby assisting the assembly of the LAT signalosome. This finding highlights vesicular trafficking to the immunological synapse as a central determinant in the translation of TCR triggering into the assembly of multimolecular signaling complexes that are known to orchestrate not only the activation of T cells, but also their development and function.

The immune synapse (IS) of effector T cells has long been known to represent a platform for the precise and effective delivery of vesicular cargo to their cell targets, in the form of lytic enzymes or cytokines. It is, however, relatively recently that we have come to appreciate the role of vesicular trafficking in the assembly and function of the IS formed by naive T cells upon encounter with an antigen-presenting cell carrying cognate MHC-associated peptide antigen.2 The unexpected discovery that the center of the bull's eye structure of the IS, which had been initially proposed to act as the site of most active signaling by concentrating engaged TCRs and key signaling components, acts rather as the end of the conveyor belt where exhausted TCRs are cleared from the surface to make space for new TCRs to become engaged, has highlighted the central role of endocytic trafficking in the assembly of a functional IS.3 Moreover, we now know that the TCR complexes that are mobilized to the IS originate not only from the plasma membrane associated pool, but also from an intracellular pool associated with recycling endosomes.4 Central membrane-associated regulators of TCR signaling, such as the kinase Lck (lymphocyte-specific protein tyrosine kinase) and the adaptor LAT, also exploit recycling to move to the IS.5,6 This mechanism has been suggested to ensure a long-lasting supply of receptors and signaling mediators at this location, which is essential to sustain signaling for the extended timeframe required for naive T-cell activation. The report by Larghi and collegues provides now evidence of a direct link between exocytic trafficking and TCR signaling at the IS by implicating the SNARE VAMP7 in the mobilization of vesicular subsynaptic LAT molecules close to TCR activation sites, where they become competent to orchestrate downstream signaling.

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  1. Department of Life Sciences, University of Siena, Siena, Italy

    Giulia Masi & Cosima T Baldari

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  1. Giulia Masi
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Correspondence to Giulia Masi or Cosima T Baldari.

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Masi, G., Baldari, C. Signaling at the immune synapse: vesicular trafficking takes the stage. Cell Mol Immunol 10, 459–462 (2013). https://doi.org/10.1038/cmi.2013.42

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