scholarly journals The Swing of Lipids at Peroxisomes and Endolysosomes in T Cell Activation

2020 ◽  
Vol 21 (8) ◽  
pp. 2859
Author(s):  
Sara G. Dosil ◽  
Amelia Rojas-Gomez ◽  
Francisco Sánchez-Madrid ◽  
Noa B. Martín-Cófreces
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Synapse Formation ◽  
Cell Receptor ◽  
Metabolic Reprogramming ◽  
Mitochondrial Activity ◽  
Oxygen Species ◽  
Immune Synapse ◽  
Antigen Presenting

The immune synapse (IS) is a well-known intercellular communication platform, organized at the interphase between the antigen presenting cell (APC) and the T cell. After T cell receptor (TCR) stimulation, signaling from plasma membrane proteins and lipids is amplified by molecules and downstream pathways for full synapse formation and maintenance. This secondary signaling event relies on intracellular reorganization at the IS, involving the cytoskeleton and components of the secretory/recycling machinery, such as the Golgi apparatus and the endolysosomal system (ELS). T cell activation triggers a metabolic reprogramming that involves the synthesis of lipids, which act as signaling mediators, and an increase of mitochondrial activity. Then, this mitochondrial activity results in elevated reactive oxygen species (ROS) production that may lead to cytotoxicity. The regulation of ROS levels requires the concerted action of mitochondria and peroxisomes. In this review, we analyze this reprogramming and the signaling implications of endolysosomal, mitochondrial, peroxisomal, and lipidic systems in T cell activation.

scholarly journals Dynein-Driven Transport of T Cell Receptor Microclusters Regulates Immune Synapse Formation and T Cell Activation

Immunity ◽  
2011 ◽  
Vol 34 (6) ◽  
pp. 919-931 ◽  
Author(s):  
Akiko Hashimoto-Tane ◽  
Tadashi Yokosuka ◽  
Kumiko Sakata-Sogawa ◽  
Machie Sakuma ◽  
Chitose Ishihara ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Synapse Formation ◽  
Cell Receptor ◽  
Immune Synapse

scholarly journals Ca2+/Calmodulin-Dependent Protein Kinase II Is a Modulator of CARMA1-Mediated NF-κB Activation

2006 ◽  
Vol 26 (14) ◽  
pp. 5497-5508 ◽  
Author(s):  
Kazuhiro Ishiguro ◽  
Todd Green ◽  
Joseph Rapley ◽  
Heather Wachtel ◽  
Cosmas Giallourakis ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Dependent Protein Kinase ◽  
Immune Synapse ◽  
Protein Kinase Ii ◽  
Dependent Protein

ABSTRACT CARMA1 is a central regulator of NF-κB activation in lymphocytes. CARMA1 and Bcl10 functionally interact and control NF-κB signaling downstream of the T-cell receptor (TCR). Computational analysis of expression neighborhoods of CARMA1-Bcl10MALT 1 for enrichment in kinases identified calmodulin-dependent protein kinase II (CaMKII) as an important component of this pathway. Here we report that Ca2+/CaMKII is redistributed to the immune synapse following T-cell activation and that CaMKII is critical for NF-κB activation induced by TCR stimulation. Furthermore, CaMKII enhances CARMA1-induced NF-κB activation. Moreover, we have shown that CaMKII phosphorylates CARMA1 on Ser109 and that the phosphorylation facilitates the interaction between CARMA1 and Bcl10. These results provide a novel function for CaMKII in TCR signaling and CARMA1-induced NF-κB activation.

The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse

2021 ◽  
Vol 14 (687) ◽  
pp. eaba0717
Author(s):  
Shunsuke Kataoka ◽  
Priyanka Manandhar ◽  
Judong Lee ◽  
Creg J. Workman ◽  
Hridesh Banerjee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Cell Receptor ◽  
Mapk Signaling ◽  
Inhibitory Protein ◽  
Immune Synapse

Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic activation, including during chronic infection and in solid tumors. Thus, Tim-3 is generally thought of as an inhibitory protein. We and others previously reported that under some circumstances, Tim-3 exerts paradoxical costimulatory activity in T cells (and other cells), including enhancement of the phosphorylation of ribosomal S6 protein. Here, we examined the upstream signaling pathways that control Tim-3–mediated increases in phosphorylated S6 in T cells. We also defined the localization of Tim-3 relative to the T cell immune synapse and its effects on downstream signaling. Recruitment of Tim-3 to the immune synapse was mediated exclusively by the transmembrane domain, replacement of which impaired the ability of Tim-3 to costimulate T cell receptor (TCR)–dependent S6 phosphorylation. Furthermore, enforced localization of the Tim-3 cytoplasmic domain to the immune synapse in a chimeric antigen receptor still enabled T cell activation. Together, our findings are consistent with a model whereby Tim-3 enhances TCR-proximal signaling under acute conditions.

scholarly journals Retrograde And Anterograde Transport Of LAT-Vesicles During The Immunological Synapse Formation: Defining The Finely-Tuned Mechanism

2020 ◽  
Author(s):  
Juan José Saez ◽  
Stéphanie Dogniaux ◽  
Massiullah Shafaq-Zadah ◽  
Ludger Johannes ◽  
Claire Hivroz ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Synapse Formation ◽  
Immunological Synapse ◽  
Retrograde Transport ◽  
Anterograde Transport ◽  
Immune Synapse ◽  
Cellular Context ◽  
Intracellular Compartments

ABSTRACTLAT is an important player of the signaling cascade induced by TCR activation. This adapter molecule is present at the plasma membrane of T lymphocytes and more abundantly in intracellular compartments. Upon T-cell activation the intracellular pool of LAT is recruited to the immune synapse (IS). We previously described two pathways controlling LAT trafficking: retrograde transport from endosomes to the TGN, and anterograde traffic from the Golgi to the IS. We address the specific role of 4 proteins, the GTPase Rab6, the t-SNARE syntaxin-16, the v-SNARE VAMP7 and the golgin GMAP210, in each pathway. Using different methods (endocytosis and Golgi trap assays, confocal and TIRF microscopy, TCR-signalosome pull down) we show that syntaxin-16 is regulating the retrograde transport of LAT whereas VAMP7 is regulating the anterograde transport. Moreover, GMAP210 and Rab6, known to contribute in both pathways, are in our cellular context specifically and respectively involved in anterograde and retrograde transport of LAT. Altogether, our data describe how retrograde and anterograde pathways coordinate LAT enrichment at the IS and point the Golgi as a central hub for the polarized recruitment of LAT to the IS. The role that this finely-tuned transport of signaling molecules plays in T-cell activation is discussed.

scholarly journals Early T cell receptor signals globally modulate ligand:receptor affinities during antigen discrimination

2017 ◽  
Vol 114 (46) ◽  
pp. 12190-12195 ◽  
Author(s):  
Rafal M. Pielak ◽  
Geoff P. O’Donoghue ◽  
Jenny J. Lin ◽  
Katherine N. Alfieri ◽  
Nicole C. Fay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Single Molecule ◽  
Cell Activation ◽  
Cell Receptor ◽  
Physical Constraints ◽  
Molecular Binding ◽  
Antigen Presenting

Antigen discrimination by T cells occurs at the junction between a T cell and an antigen-presenting cell. Juxtacrine binding between numerous adhesion, signaling, and costimulatory molecules defines both the topographical and lateral geometry of this cell–cell interface, within which T cell receptor (TCR) and peptide major histocompatibility complex (pMHC) interact. These physical constraints on receptor and ligand movement have significant potential to modulate their molecular binding properties. Here, we monitor individual ligand:receptor binding and unbinding events in space and time by single-molecule imaging in live primary T cells for a range of different pMHC ligands and surface densities. Direct observations of pMHC:TCR and CD80:CD28 binding events reveal that the in situ affinity of both pMHC and CD80 ligands for their respective receptors is modulated by the steady-state number of agonist pMHC:TCR interactions experienced by the cell. By resolving every single pMHC:TCR interaction it is evident that this cooperativity is accomplished by increasing the kinetic on-rate without altering the off-rate and has a component that is not spatially localized. Furthermore, positive cooperativity is observed under conditions where the T cell activation probability is low. This TCR-mediated feedback is a global effect on the intercellular junction. It is triggered by the first few individual pMHC:TCR binding events and effectively increases the efficiency of TCR scanning for antigen before the T cell is committed to activation.

scholarly journals T cell activation enhancement by endogenous pMHC acts for both weak and strong agonists but varies with differentiation state

2007 ◽  
Vol 204 (11) ◽  
pp. 2747-2757 ◽  
Author(s):  
Pia P. Yachi ◽  
Carina Lotz ◽  
Jeanette Ampudia ◽  
Nicholas R.J. Gascoigne
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Endogenous Peptides ◽  
Foreign Peptide ◽  
Antigen Presenting

T cells are extremely sensitive in their ability to find minute amounts of antigenic peptide in the midst of many endogenous peptides presented on an antigen-presenting cell. The role of endogenous peptides in the recognition of foreign peptide and hence in T cell activation has remained controversial for CD8+ T cell activation. We showed previously that in a CD8+ T cell hybridoma, nonstimulatory endogenous peptides enhance T cell sensitivity to antigen by increasing the coreceptor function of CD8. However, others were not able to detect such enhancement in naive and activated CD8+ T cells. Here, we show that endogenous peptides substantially enhance the ability of T cells to detect antigen, an effect measurable by up-regulation of activation or maturation markers and by increased effector function. This enhancement is most pronounced in thymocytes, moderate in naive T cells, and mild in effector T cells. The importance of endogenous peptides is inversely proportional to the agonist activity of the stimulatory peptide presented. Unlike for CD4+ T cells, the T cell receptor of CD8+ T cells does not distinguish between endogenous peptides for their ability to enhance antigen recognition.

scholarly journals Requirements for Peptide-induced T Cell Receptor Downregulation on Naive CD8+ T Cells

1997 ◽  
Vol 185 (4) ◽  
pp. 641-652 ◽  
Author(s):  
Zeling Cai ◽  
Hidehiro Kishimoto ◽  
Anders Brunmark ◽  
Michael R. Jackson ◽  
Per A. Peterson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Biological Significance ◽  
Cell Receptor ◽  
Metabolic Inhibitors ◽  
Histocompatibility Complex ◽  
Antigen Presenting

The requirements for inducing downregulation of α/β T cell receptor (TCR) molecules on naive major histocompatibility complex class I–restricted T cells was investigated with 2C TCR transgenic mice and defined peptides as antigen. Confirming previous results, activation of 2C T cells in response to specific peptides required CD8 expression on the responder cells and was heavily dependent upon costimulation provided by either B7-1 or ICAM-1 on antigen-presenting cells (APC). These stringent requirements did not apply to TCR downregulation. Thus, TCR downregulation seemed to depend solely on TCR/peptide/interaction and did not require either CD8 or B7-1 expression; ICAM-1 potentiated TCR downregulation, but only with limiting doses of peptides. TCR downregulation was most prominent with high affinity peptides and appeared to be neither obligatory nor sufficient for T cell activation. In marked contrast to T cell activation, TCR downregulation was resistant to various metabolic inhibitors. The biological significance of TCR downregulation is unclear, but could be a device for protecting T cells against excessive signaling.

scholarly journals Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration

Blood ◽  
2016 ◽  
Vol 128 (4) ◽  
pp. 563-573 ◽  
Author(s):  
Marta Pasikowska ◽  
Elisabeth Walsby ◽  
Benedetta Apollonio ◽  
Kirsty Cuthill ◽  
Elizabeth Phillips ◽  
...  
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Synapse Formation ◽  
Immune Synapse ◽  
Circulating Cells ◽  
Immunologic Function ◽  
Key Points

Key Points LN-derived CLL cells have increased capacity for T-cell activation and superior immune synapse formation compared with those from PB. Enhanced CLL cell immunologic function is also linked to PB circulating cells with the propensity to migrate.

scholarly journals LFA-1 and Kindlin-3 enable the collaborative transport of SLP-76 microclusters by myosin and dynein motors

2021 ◽  
Author(s):  
Keith P. Eidell ◽  
Alenka Lovy ◽  
Nicholas R. Sylvain ◽  
Frank A. Scangarello ◽  
Hayley I. Muendlein ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Ligand Density ◽  
Immune Synapse ◽  
Dynein Motor ◽  
Myosin Filaments ◽  
Actomyosin Contraction ◽  
Centripetal Movement

Integrin engagement within the immune synapse enhances T cell activation, but our understanding of this process is incomplete. In response to T cell receptor (TCR) ligation, SLP-76 (LCP2), ADAP (FYB), and SKAP-55 (SKAP1) are recruited into microclusters and activate integrins via the effectors Talin-1 and Kindlin-3. We postulated that integrins influence the centripetal transport and signaling of SLP-76 microclusters via these linkages. We show that contractile myosin filaments surround and are co-transported with SLP-76 microclusters, and that TCR ligand density governs the centripetal movement of both structures. Centripetal transport requires formin activity, actomyosin contraction, microtubule integrity, and dynein motor function. Although immobilized VLA-4 (a4b1) and LFA-1 (aLb2) ligands arrest the centripetal movement of SLP-76 microclusters and myosin filaments, VLA-4 acts distally, while LFA-1 acts in the lamellum. Integrin b2, Kindlin-3, and Zyxin are required for complete centripetal transport, while integrin b1 and Talin-1 are not. CD69 upregulation is similarly dependent on integrin b2, Kindlin-3, and Zyxin, but not Talin-1. These findings highlight the integration of cytoskeletal systems within the immune synapse and reveal extracellular ligand-independent roles for LFA-1 and Kindlin-3.

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