scholarly journals IGSF4 is a novel TCR ζ-chain–interacting protein that enhances TCR-mediated signaling

2011 ◽  
Vol 208 (12) ◽  
pp. 2545-2560 ◽  
Author(s):  
Hye-Ran Kim ◽  
Byeong-Hun Jeon ◽  
Hyun-Su Lee ◽  
Sin-Hyeog Im ◽  
Masatake Araki ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Transmembrane Domain ◽  
Cell Receptor ◽  
Immunoglobulin Superfamily ◽  
Tcr Signaling ◽  
Cell Functions ◽  
Cell Immunity

Immunoglobulin superfamily member 4 (IGSF4) is a known ligand of CRTAM, a receptor expressed in activated NKT and CD8+ T cells, but its function in T cell immunity has not been elucidated. In this study, we show that IGSF4 directly interacts with the T cell receptor (TCR) ζ-chain and enhances TCR signaling by enhancing ζ-chain phosphorylation. Ectopic overexpression of IGSF4 enhances TCR-mediated T cell activation. In contrast, IGSF4 knockdown shows a dramatic decrease in markers associated with T cell activation compared with those in control small interfering RNA. The transmembrane domain is essential for TCR ζ-chain association and clustering to the immunological synapse, and the ectodomain is associated with T cell interaction with antigen-presenting cells (APCs). IGSF4-deficient mice have impaired TCR-mediated thymocyte selection and maturation. Furthermore, these mice reveal attenuated effector T cell functions accompanied by defective TCR signaling. Collectively, the results indicate that IGSF4 plays a central role in T cell functioning by dual independent mechanisms, control of TCR signaling and control of T cell–APC interaction.

scholarly journals Micro–adhesion rings surrounding TCR microclusters are essential for T cell activation

2016 ◽  
Vol 213 (8) ◽  
pp. 1609-1625 ◽  
Author(s):  
Akiko Hashimoto-Tane ◽  
Machie Sakuma ◽  
Hiroshi Ike ◽  
Tadashi Yokosuka ◽  
Yayoi Kimura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adhesion Molecules ◽  
Focal Adhesion ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Ring Structure ◽  
Cell Functions

The immunological synapse (IS) formed at the interface between T cells and antigen-presenting cells represents a hallmark of initiation of acquired immunity. T cell activation is initiated at T cell receptor (TCR) microclusters (MCs), in which TCRs and signaling molecules assemble at the interface before IS formation. We found that each TCR-MC was transiently bordered by a ring structure made of integrin and focal adhesion molecules in the early phase of activation, which is similar in structure to the IS in microscale. The micro–adhesion ring is composed of LFA-1, focal adhesion molecules paxillin and Pyk2, and myosin II (MyoII) and is supported by F-actin core and MyoII activity through LFA-1 outside-in signals. The formation of the micro–adhesion ring was transient but especially sustained upon weak TCR stimulation to recruit linker for activation of T cells (LAT) and SLP76. Perturbation of the micro–adhesion ring induced impairment of TCR-MC development and resulted in impaired cellular signaling and cell functions. Thus, the synapse-like structure composed of the core TCR-MC and surrounding micro–adhesion ring is a critical structure for initial T cell activation through integrin outside-in signals.

The actin cloud induced by LFA-1–mediated outside-in signals lowers the threshold for T-cell activation

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 168-175 ◽  
Author(s):  
Jun-ichiro Suzuki ◽  
Sho Yamasaki ◽  
Jennifer Wu ◽  
Gary A. Koretzky ◽  
Takashi Saito
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Cloud Formation ◽  
Lymphocyte Function ◽  
Tcr Signaling

Abstract The dynamic rearrangement of the actin cytoskeleton plays critical roles in T-cell receptor (TCR) signaling and immunological synapse (IS) formation in T cells. Following actin rearrangement in T cells upon TCR stimulation, we found a unique ring-shaped reorganization of actin called the “actin cloud,” which was specifically induced by outside-in signals through lymphocyte function–associated antigen-1 (LFA-1) engagement. In T-cell–antigen-presenting cell (APC) interactions, the actin cloud is generated in the absence of antigen and localized at the center of the T-cell–APC interface, where it accumulates LFA-1 and tyrosine-phosphorylated proteins. The LFA-1–induced actin cloud formation involves ADAP (adhesion- and degranulation-promoting adaptor protein) phosphorylation, LFA-1/ADAP assembly, and c-Jun N-terminal kinase (JNK) activation, and occurs independent of TCR and its proximal signaling. The formation of the actin cloud lowers the threshold for subsequent T-cell activation. Thus, the actin cloud induced by LFA-1 engagement may serve as a possible platform for LFA-1–mediated costimulatory function for T-cell activation.

scholarly journals CD45 pre-exclusion from the tips of T cell microvilli prior to antigen recognition

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yunmin Jung ◽  
Lai Wen ◽  
Amnon Altman ◽  
Klaus Ley
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Transmembrane Domain ◽  
Tyrosine Phosphatase ◽  
Adaptive Immune Response ◽  
Super Resolution ◽  
Cell Receptor

AbstractThe tyrosine phosphatase CD45 is a major gatekeeper for restraining T cell activation. Its exclusion from the immunological synapse (IS) is crucial for T cell receptor (TCR) signal transduction. Here, we use expansion super-resolution microscopy to reveal that CD45 is mostly pre-excluded from the tips of microvilli (MV) on primary T cells prior to antigen encounter. This pre-exclusion is diminished by depleting cholesterol or by engineering the transmembrane domain of CD45 to increase its membrane integration length, but is independent of the CD45 extracellular domain. We further show that brief MV-mediated contacts can induce Ca2+ influx in mouse antigen-specific T cells engaged by antigen-pulsed antigen presenting cells (APC). We propose that the scarcity of CD45 phosphatase activity at the tips of MV enables or facilitates TCR triggering from brief T cell-APC contacts before formation of a stable IS, and that these MV-mediated contacts represent the earliest step in the initiation of a T cell adaptive immune response.

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.

scholarly journals CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 580-588 ◽  
Author(s):  
Kathrin Gollmer ◽  
François Asperti-Boursin ◽  
Yoshihiko Tanaka ◽  
Klaus Okkenhaug ◽  
Bart Vanhaesebroeck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Early Time ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activation Markers

Abstract CD4+ T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)–transgenic (tg) CD4+ T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3KδD910A/D910A or PI3Kγ-deficient TCR-tg CD4+ T cells showed similar responsiveness to CCL21 costimulation as control CD4+ T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4+ T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca2+ signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation.

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 Stomatin-like Protein 2 Links Mitochondria to T-Cell Receptor Signalosomes at the Immunological Synapse and Enhances T-Cell Activation

2007 ◽  
Author(s):  
Mark Kirchhof ◽  
Luan Chau ◽  
Caitlin Lemke ◽  
Santosh Vardhana ◽  
Peter Darlington ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor

scholarly journals Comparative analysis of B7-1 and B7-2 costimulatory ligands: expression and function.

1994 ◽  
Vol 180 (2) ◽  
pp. 631-640 ◽  
Author(s):  
K S Hathcock ◽  
G Laszlo ◽  
C Pucillo ◽  
P Linsley ◽  
R J Hodes
Keyword(s):  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Types ◽  
Cell Receptor ◽  
Costimulatory Molecules ◽  
Tcr Signaling ◽  
And Function

Antigen-specific T cell activation requires the engagement of the T cell receptor (TCR) with antigen as well as the engagement of appropriate costimulatory molecules. The most extensively characterized pathway of costimulation has been that involving the interaction of CD28 and CTLA4 on the T cell with B7 (now termed B7-1) on antigen presenting cells. Recently, B7-2 a second costimulatory ligand for CTLA4, was described, demonstrating the potential complexity of costimulatory interactions. This report examines and compares the expression and function of B7-1 and B7-2. Overall these results indicate that (a) B7-1 and B7-2 can be expressed by multiple cell types, including B cells, T cells, macrophages, and dendritic cells, all of which are therefore candidate populations for delivering costimulatory signals mediated by these molecules; (b) stimulating B cells with either LPS or anti-IgD-dextran induced expression of both B7-1 and B7-2, and peak expression of both costimulatory molecules occurred after 18-42 h of culture. Expression of B7-2 on these B cell populations was significantly higher than expression of B7-1 at all times assayed after stimulation; (c) blocking of B7-2 costimulatory activity inhibited TCR-dependent T cell proliferation and cytokine production, without affecting early consequences of TCR signaling such as induction of CD69 or interleukin 2 receptor alpha (IL-2R alpha); and (d) expression of B7-1 and of B7-2 can be regulated by a variety of stimuli. Moreover, expression of B7-1 and B7-2 can be independently regulated by the same stimulus, providing an additional complexity in the mechanisms available for regulating costimulation and hence immune response.

scholarly journals Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells

2017 ◽  
Vol 114 (30) ◽  
pp. E6117-E6126 ◽  
Author(s):  
Thomas C. J. Tan ◽  
John Knight ◽  
Thomas Sbarrato ◽  
Kate Dudek ◽  
Anne E. Willis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Ribosome Biogenesis ◽  
Cell Activation ◽  
Mrna Translation ◽  
Protein Translation ◽  
Cell Receptor ◽  
Tcr Signaling

Global transcriptomic and proteomic analyses of T cells have been rich sources of unbiased data for understanding T-cell activation. Lack of full concordance of these datasets has illustrated that important facets of T-cell activation are controlled at the level of translation. We undertook translatome analysis of CD8 T-cell activation, combining polysome profiling and microarray analysis. We revealed that altering T-cell receptor stimulation influenced recruitment of mRNAs to heavy polysomes and translation of subsets of genes. A major pathway that was compromised, when TCR signaling was suboptimal, was linked to ribosome biogenesis, a rate-limiting factor in both cell growth and proliferation. Defective TCR signaling affected transcription and processing of ribosomal RNA precursors, as well as the translation of specific ribosomal proteins and translation factors. Mechanistically, IL-2 production was compromised in weakly stimulated T cells, affecting the abundance of Myc protein, a known regulator of ribosome biogenesis. Consequently, weakly activated T cells showed impaired production of ribosomes and a failure to maintain proliferative capacity after stimulation. We demonstrate that primary T cells respond to various environmental cues by regulating ribosome biogenesis and mRNA translation at multiple levels to sustain proliferation and differentiation.

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