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

• Verfasst von: Zurli, Vanessa [VerfasserIn]
• Verfasst von: Montecchi, Tommaso [VerfasserIn]
• Verfasst von: Heilig, Raphael [VerfasserIn]
• Verfasst von: Poschke, Isabel [VerfasserIn]
• Verfasst von: Volkmar, Michael [VerfasserIn]
• Verfasst von: Wimmer, Giuliana [VerfasserIn]
• Verfasst von: Boncompagni, Gioia [VerfasserIn]
• Verfasst von: Turacchio, Gabriele [VerfasserIn]
• Verfasst von: D’Elios, Mario Milco [VerfasserIn]
• Verfasst von: Campoccia, Giuseppe [VerfasserIn]
• Verfasst von: Resta, Nicoletta [VerfasserIn]
• Verfasst von: Offringa, Rienk [VerfasserIn]
• Verfasst von: Fischer, Roman [VerfasserIn]
• Verfasst von: Acuto, Oreste [VerfasserIn]
• Verfasst von: Baldari, Cosima Tatiana [VerfasserIn]
• Verfasst von: Kabanova, Anna [VerfasserIn]
• Titel: Phosphoproteomics of CD2 signaling reveals AMPK-dependent regulation of lytic granule polarization in cytotoxic T cells
• Verf.angabe: Vanessa Zurli, Tommaso Montecchi, Raphael Heilig, Isabel Poschke, Michael Volkmar, Giuliana Wimmer, Gioia Boncompagni, Gabriele Turacchio, Mario Milco D’Elios, Giuseppe Campoccia, Nicoletta Resta, Rienk Offringa, Roman Fischer, Oreste Acuto, Cosima Tatiana Baldari, Anna Kabanova
• E-Jahr: 2020
• Jahr: 12 May 2020
• Umfang: ? S.
• Fussnoten: Gesehen am 02.07.2020
• Titel Quelle: Enthalten in: Science signaling
• Ort Quelle: Washington, DC [u.a.] : Assoc., 2008
• Jahr Quelle: 2020
• Band/Heft Quelle: 13(2020,631) Artikel-Nummer eaaz1965, ? Seiten
• ISSN Quelle: 1937-9145
• DOI: doi:10.1126/scisignal.aaz1965
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1703272994

Abstract

AMPing up cytotoxicity - Cytotoxic T cells (CTLs) form an immune synapse at the interface formed with their target cells and then reorient intracellular lytic granules toward the contact site to ensure efficient killing. Zurli et al. found that stimulation of the receptor CD2 on CTLs by CD58 on target B cells enhanced T cell receptor signaling during immune synapse formation. Phosphoproteomics analysis showed that CD2 stimulation led to activation of the metabolism-regulating kinase AMPK on lysosomes, which promoted lytic granule translocation to the immune synapse. Together, these findings suggest that targeting the CD2-AMPK axis may enhance CTL activity. - 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. - CD2-stimulated AMPK activation mediates lytic granule organization in cytotoxic T cells. - CD2-stimulated AMPK activation mediates lytic granule organization in cytotoxic T cells.