Phosphoproteomics of CD2 signaling reveals AMPK-dependent regulation of lytic granule polarization in cytotoxic T cells

Understanding the costimulatory signaling that enhances the activity of cytotoxic T cells (CTLs) could identify potential targets for immunotherapy. Here, we report that CD2 costimulation plays a critical role in target cell killing by freshly isolated human CD8 T cells, which represent a challengin...

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Veröffentlicht in:Science signaling 2020-05, Vol.13 (631)
Hauptverfasser: Zurli, Vanessa, Montecchi, Tommaso, Heilig, Raphael, Poschke, Isabel, Volkmar, Michael, Wimmer, Giuliana, Boncompagni, Gioia, Turacchio, Gabriele, D'Elios, Mario Milco, Campoccia, Giuseppe, Resta, Nicoletta, Offringa, Rienk, Fischer, Roman, Acuto, Oreste, Baldari, Cosima Tatiana, Kabanova, Anna
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container_issue 631
container_start_page
container_title Science signaling
container_volume 13
creator Zurli, Vanessa
Montecchi, Tommaso
Heilig, Raphael
Poschke, Isabel
Volkmar, Michael
Wimmer, Giuliana
Boncompagni, Gioia
Turacchio, Gabriele
D'Elios, Mario Milco
Campoccia, Giuseppe
Resta, Nicoletta
Offringa, Rienk
Fischer, Roman
Acuto, Oreste
Baldari, Cosima Tatiana
Kabanova, Anna
description Understanding the costimulatory signaling that enhances the activity of cytotoxic T cells (CTLs) could identify potential targets for immunotherapy. Here, we report that CD2 costimulation plays a critical role in target cell killing by freshly isolated human CD8 T cells, which represent a challenging but valuable model to gain insight into CTL biology. We found that CD2 stimulation critically enhanced signaling by the T cell receptor in the formation of functional immune synapses by promoting the polarization of lytic granules toward the microtubule-organizing center (MTOC). To gain insight into the underlying mechanism, we explored the CD2 signaling network by phosphoproteomics, which revealed 616 CD2-regulated phosphorylation events in 373 proteins implicated in the regulation of vesicular trafficking, cytoskeletal organization, autophagy, and metabolism. Signaling by the master metabolic regulator AMP-activated protein kinase (AMPK) was a critical node in the CD2 network, which promoted granule polarization toward the MTOC in CD8 T cells. Granule trafficking was driven by active AMPK enriched on adjacent lysosomes, revealing previously uncharacterized signaling cross-talk between vesicular compartments in CD8 T cells. Our results thus establish CD2 signaling as key for mediating cytotoxic killing and granule polarization in freshly isolated CD8 T cells and strengthen the rationale to choose CD2 and AMPK as therapeutic targets to enhance CTL activity.
doi_str_mv 10.1126/scisignal.aaz1965
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subjects AMP
AMP-activated protein kinase
Autophagy
CD58 antigen
CD8 antigen
Crosstalk
Cytoskeleton
Cytotoxicity
Granular materials
Immunological synapses
Immunotherapy
Kinases
Lymphocytes
Lymphocytes B
Lymphocytes T
Lysosomes
Metabolism
Phagocytosis
Phosphorylation
Polarization
Proteins
Receptors
Signaling
Stimulation
Synapses
T cell receptors
Target recognition
Therapeutic applications
Toxicity
Translocation
title Phosphoproteomics of CD2 signaling reveals AMPK-dependent regulation of lytic granule polarization in cytotoxic T cells
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