scholarly journals CD8+ Tumor-Infiltrating T Cells Are Deficient in Perforin-Mediated Cytolytic Activity Due to Defective Microtubule-Organizing Center Mobilization and Lytic Granule Exocytosis

2001 ◽  
Vol 167 (9) ◽  
pp. 5042-5051 ◽  
Author(s):  
Sasa Radoja ◽  
Masanao Saio ◽  
David Schaer ◽  
Mythili Koneru ◽  
Stanislav Vukmanovic ◽  
...  
Keyword(s):  
T Cells ◽  
Cytolytic Activity ◽  
Microtubule Organizing Center ◽  
Granule Exocytosis ◽  
Organizing Center ◽  
Lytic Granule

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

2020 ◽  
Vol 13 (631) ◽  
pp. eaaz1965 ◽  
Author(s):  
Vanessa Zurli ◽  
Tommaso Montecchi ◽  
Raphael Heilig ◽  
Isabel Poschke ◽  
Michael Volkmar ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic T Cells ◽  
Critical Role ◽  
Underlying Mechanism ◽  
Cell Receptor ◽  
Microtubule Organizing Center ◽  
Lytic Granules ◽  
Organizing Center ◽  
Lytic Granule ◽  
Insight Into

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.

scholarly journals Stathmin Regulates Microtubule Dynamics and Microtubule Organizing Center Polarization in Activated T Cells

2012 ◽  
Vol 188 (11) ◽  
pp. 5421-5427 ◽  
Author(s):  
Erin L. Filbert ◽  
Marie Le Borgne ◽  
Joseph Lin ◽  
John E. Heuser ◽  
Andrey S. Shaw
Keyword(s):  
T Cells ◽  
Microtubule Dynamics ◽  
Microtubule Organizing Center ◽  
Activated T Cells ◽  
Organizing Center

Imaging of plasmacytoid dendritic cell interactions with T cells

Blood ◽  
2009 ◽  
Vol 113 (1) ◽  
pp. 75-84 ◽  
Author(s):  
María Mittelbrunn ◽  
Gloria Martínez del Hoyo ◽  
María López-Bravo ◽  
Noa B. Martín-Cofreces ◽  
Alix Scholer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Time Lapse ◽  
Cell Interactions ◽  
Type I ◽  
Microtubule Organizing Center ◽  
Immune Synapse ◽  
Organizing Center

Abstract Plasmacytoid dendritic cells (pDCs) efficiently produce type I interferon and participate in adaptive immune responses, although the molecular interactions between pDCs and antigen-specific T cells remain unknown. This study examines immune synapse (IS) formation between murine pDCs and CD4+ T cells. Mature pDCs formed canonical ISs, involving relocation to the contact site of the microtubule-organizing center, F-actin, protein kinase C-θ, and pVav, and activation of early signaling molecules in T cells. However, immature pDCs were less efficient at forming conjugates with T cells and inducing IS formation, microtubule-organizing center translocation, and T-cell signaling and activation. Time-lapse videomicroscopy and 2-photon in vivo imaging of pDC–T-cell interactions revealed that immature pDCs preferentially mediated transient interactions, whereas mature pDCs promoted more stable contacts. Our data indicate that, under steady-state conditions, pDCs preferentially establish transient contacts with naive T cells and show a very modest immunogenic capability, whereas on maturation, pDCs are able to form long-lived contacts with T cells and significantly enhance their capacity to activate these lymphocytes.

scholarly journals Cytokine Secretion by CD4+ T Cells at the Immunological Synapse Requires Cdc42-Dependent Local Actin Remodeling but Not Microtubule Organizing Center Polarity

2012 ◽  
Vol 189 (5) ◽  
pp. 2159-2168 ◽  
Author(s):  
Karine Chemin ◽  
Armelle Bohineust ◽  
Stéphanie Dogniaux ◽  
Marie Tourret ◽  
Sarah Guégan ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Immunological Synapse ◽  
Cytokine Secretion ◽  
Microtubule Organizing Center ◽  
Actin Remodeling ◽  
Organizing Center

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

2019 ◽  
Author(s):  
Vanessa Zurli ◽  
Tommaso Montecchi ◽  
Raphael Heilig ◽  
Isabel Poschke ◽  
Michael Volkmar ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic T Cells ◽  
Critical Role ◽  
Cell Receptor ◽  
Microtubule Organizing Center ◽  
Lytic Granules ◽  
Cytoskeleton Organization ◽  
Depth Analysis ◽  
Organizing Center ◽  
Insight Into

SummaryThe in-depth analysis of costimulatory signaling enhancing the activity of cytotoxic T cells (CTLs) represents a major approach towards immunotherapy development. Here we report that CD2 costimulation plays a critical role in killing by freshly isolated human CTLs, which represent a challenging but valuable study model to gain insight into CTL biology. We show that CD2 triggering critically aids signaling by the T cell receptor in the formation of functional immune synapses by promoting the polarization of lytic granules towards the microtubule-organizing center (MTOC). To gain insight into the underlying elusive 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, cytoskeleton organization, autophagy and metabolism. Strikingly, signaling by the master metabolic regulator AMP-activated protein kinase (AMPK) represents a functionally critical node of the CD2 network which regulates granule polarization towards the MTOC in CTLs. Granule trafficking is driven by active AMPK enriched on adjacent lysosomes, illustrating a novel signaling cross-talk between vesicular compartments in CTLs. Our results thus establish CD2 signaling as key for regulating cytotoxic killing and granule polarization in freshly isolated CTLs and strengthens the rationale to choose CD2 and AMPK as therapeutic targets to boost CTL activity.

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