scholarly journals HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation

2016 ◽  
Vol 90 (23) ◽  
pp. 10513-10526 ◽  
Author(s):  
Jing Deng ◽  
Yu-ya Mitsuki ◽  
Guomiao Shen ◽  
Jocelyn C. Ray ◽  
Claudia Cicala ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Activation Process ◽  
Hiv Envelope

ABSTRACTHIV is transmitted most efficiently from cell to cell, and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits immunological synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell immunological synapse affects synapse formation and intracellular signaling to impact the downstream T cell activation events. CD4 T cells were applied to supported lipid bilayers that were reconstituted with HIV Env gp120, anti-T cell receptor (anti-TCR) monoclonal antibody, and ICAM-1 to represent the surface of HIV Env-bearing antigen-presenting cells. The results showed that the HIV Env did not disrupt immunological synapse formation. Instead, the HIV Env accumulated with TCR at the center of the synapse, altered the kinetics of TCR recruitment to the synapse and affected synapse morphology over time. The HIV Env also prolonged Lck phosphorylation at the synapse and enhanced TCR-induced CD69 upregulation, interleukin-2 secretion, and proliferation to promote virus infection. These results suggest that HIV uses the immunological synapse as a conduit not only for selective virus transmission to activated CD4 T cells but also for boosting the T cell activation state, thereby increasing its likelihood of undergoing productive replication in targeted CD4 T cells.IMPORTANCEThere are about two million new HIV infections every year. A better understanding of how HIV is transmitted to susceptible cells is critical to devise effective strategies to prevent HIV infection. Activated CD4 T cells are preferentially infected by HIV, although how this is accomplished is not fully understood. This study examined whether HIV co-opts the normal T cell activation process through the so-called immunological synapse. We found that the HIV envelope is recruited to the center of the immunological synapse together with the T cell receptor and enhances the T cell receptor-induced activation of CD4 T cells. Heightened cellular activation promotes the capacity of CD4 T cells to support productive HIV replication. This study provides evidence of the exploitation of the normal immunological synapse and T cell activation process by HIV to boost the activation state of targeted CD4 T cells and promote the infection of these cells.

CD4 + T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T‐cell receptor repertoires

2019 ◽  
Vol 49 (6) ◽  
pp. 653-662
Author(s):  
Ryo Nakagawa ◽  
Ryosuke Muroyama ◽  
Chisato Saeki ◽  
Tsunekazu Oikawa ◽  
Yoshimi Kaise ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cell Receptor ◽  
Differentially Expressed ◽  
Primary Biliary Cholangitis

scholarly journals Cytokine-Induced Src Homology 2 Protein (Cis) Promotes T Cell Receptor–Mediated Proliferation and Prolongs Survival of Activated T Cells

2000 ◽  
Vol 191 (6) ◽  
pp. 985-994 ◽  
Author(s):  
Suling Li ◽  
Shangwu Chen ◽  
Xiufeng Xu ◽  
Anette Sundstedt ◽  
Kajsa M. Paulsson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cell Receptor ◽  
Cytokine Signaling ◽  
Src Homology 2 ◽  
Src Homology

Members of the suppressor of cytokine signaling (SOCS) family were discovered as negative regulators of cytokine signaling by inhibition of the Janus kinase–signal transducer and activator of transcription (Jak-STAT) pathway. Among them, cytokine-induced Src homology 2 (SH2) protein (CIS) was found to inhibit the interleukin 3– and erythropietin-mediated STAT5 signaling pathway. However, involvement of SOCS proteins in other signaling pathways is still unknown. This study shows that the expression of CIS is selectively induced in T cells after T cell receptor (TCR) stimulation. In transgenic mice, with selective expression of CIS in CD4 T cells, elevated CIS strongly promotes TCR-mediated proliferation and cytokine production in vitro, and superantigen-induced T cell activation in vivo. Forced expression of CIS also prolongs survival of CD4 T cells after TCR activation. Molecular events immediately downstream from the TCR are not changed in CIS-expressing CD4 T cells, but activation of mitogen-activated protein (MAP) kinase pathways by TCR stimulation is significantly enhanced. Together with the increased MAP kinase activation, a direct interaction of CIS and protein kinase Cθ was also demonstrated. These results suggest that CIS is one of the important regulators of TCR-mediated T cell activation. The functions of CIS, enhancing TCR signaling and inhibiting cytokine signaling, may be important in the regulation of immune response and homeostasis.

Sphingomyelin breakdown in T cells: role in activation, effector functions and immunoregulation

2015 ◽  
Vol 396 (6-7) ◽  
pp. 749-758 ◽  
Author(s):  
Niklas Beyersdorf ◽  
Nora Müller
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Activity ◽  
Cell Receptor ◽  
Cell Mediated Immunity ◽  
Functional Responses

Abstract Host T cell activation, a key step in obtaining adaptive immunity against pathogens, is initiated by the binding of the T cell receptor to a foreign antigenic peptide presented by the major histocompatibility complex on the surface of an antigen-presenting cell and, consequently, formation of an immunological synapse. Within the immunological synapse, the engagement of the T cell receptor in cooperation with simultaneous ligation of co-stimulatory molecules induces a precisely organized cascade of signaling events and pathways that regulate clonal expansion and differentiation of naïve T cells into effector T cells contributing to pathogen clearance. The biochemical changes that underlie T cell activation and differentiation, however, not only involve proteins but also lipids. In particular, catabolic cleavage of sphingomyelin generating ceramide can substantially influence functional responses in cells of the immune system. Changes in sphingomyelin and ceramide content have been reported to directly impact on membrane physiology, thus modifying signal transmission and interfering with diverse aspects of T cell activity. In this review we will focus on sphingomyelin breakdown/ceramide generation in T cells with regard to their function and development of T cell-mediated immunity.

scholarly journals Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

2008 ◽  
Vol 19 (7) ◽  
pp. 2802-2817 ◽  
Author(s):  
Valarie A. Barr ◽  
Kelsie M. Bernot ◽  
Sonal Srikanth ◽  
Yousang Gwack ◽  
Lakshmi Balagopalan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Dynamic Movement ◽  
Immunological Synapses

The proteins STIM1 and Orai1 are the long sought components of the store-operated channels required in T-cell activation. However, little is known about the interaction of these proteins in T-cells after engagement of the T-cell receptor. We found that T-cell receptor engagement caused STIM1 and Orai1 to colocalize in puncta near the site of stimulation and accumulate in a dense structure on the opposite side of the T-cell. FRET measurements showed a close interaction between STIM1 and Orai1 both in the puncta and in the dense cap-like structure. The formation of cap-like structures did not entail rearrangement of the entire endoplasmic reticulum. Cap formation depended on TCR engagement and tyrosine phosphorylation, but not on channel activity or Ca2+ influx. These caps were very dynamic in T-cells activated by contact with superantigen pulsed B-cells and could move from the distal pole to an existing or a newly forming immunological synapse. One function of this cap may be to provide preassembled Ca2+ channel components to existing and newly forming immunological synapses.

scholarly journals Disc Large Homolog 1 Is Critical for Early T Cell Receptor Micro Cluster Formation and Activation in Human T Cells

Vaccines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1446
Author(s):  
June Guha ◽  
Raj Chari
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Signaling ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Synapse Formation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
T Cell Signaling

T cell activation by antigen involves multiple sequential steps, including T cell receptor-microcluster TCR-(MC) formation, immunological synapse formation, and phosphorylation of mediators downstream of the TCR. The adaptor protein, Disc Large Homolog 1 (DLG1), is known to regulate proximal TCR signaling and, in turn, T cell activation, acting as a molecular chaperone that organizes specific kinases downstream of antigen recognition. In this study, we used knockdown and knockout technologies in human primary T cells and a human T cell line to demonstrate the role of DLG1 in proximal T cell signaling. High-end confocal microscopy was used for pictorial representation of T cell micro-clusters and colocalization studies. From all these studies, we could demonstrate that DLG1 functions even earlier than immunological synapse formation, to regulate T cell activation by promoting TCR-MC formation. Moreover, we found that DLG1 can act as a bridge between the TCR-ζ chain and ZAP70 while inhibiting binding of the phosphatase SHP1 to TCR-ζ. Together, these effects drive dysregulation of T cell activation in DLG1-deficient T cells. Overall, the activation and survival status of T cell is a critical determinant of effective vaccine response, and DLG1-mediated T cell signaling events can be a driving factor for improving vaccine-designing strategies.

scholarly journals T cell receptor zeta/CD3-p59fyn(T)-associated p120/130 binds to the SH2 domain of p59fyn(T).

1993 ◽  
Vol 178 (6) ◽  
pp. 2107-2113 ◽  
Author(s):  
A J da Silva ◽  
O Janssen ◽  
C E Rudd
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
T Complex

Intracellular signaling from the T cell receptor (TCR)zeta/CD3 complex is likely to be mediated by associated protein tyrosine kinases such as p59fyn(T), ZAP-70, and the CD4:p56lck and CD8:p56lck coreceptors. The nature of the signaling cascade initiated by these kinases, their specificities, and downstream targets remain to be elucidated. The TCR-zeta/CD3:p59fyn(T) complex has previously been noted to coprecipitate a 120/130-kD doublet (p120/130). This intracellular protein of unknown identity associates directly with p59fyn(T) within the receptor complex. In this study, we have shown that this interaction with p120/130 is specifically mediated by the SH2 domain (not the fyn-SH3 domain) of p59fyn(T). Further, based on the results of in vitro kinase assays, p120/130 appears to be preferentially associated with p59fyn(T) in T cells, and not with p56lck. Antibody reprecipitation studies identified p120/130 as a previously described 130-kD substrate of pp60v-src whose function and structure is unknown. TCR-zeta/CD3 induced activation of T cells augmented the tyrosine phosphorylation of p120/130 in vivo as detected by antibody and GST:fyn-SH2 fusion proteins. p120/130 represents the first identified p59fyn(T):SH2 binding substrate in T cells, and as such is likely to play a key role in the early events of T cell 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.

FLT3-Kinase Inhibitors Quizartinib and Midostaurin Do Not Impair T-Cell Reactivity and Activation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1045-1045
Author(s):  
Denise Wolleschak ◽  
Thomas S. Mack ◽  
Florian Perner ◽  
Tina M Schnoeder ◽  
Marie-Christine Wagner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Kinase Inhibitors ◽  
Cell Receptor ◽  
Receptor Signaling ◽  
T Cell Receptor Signaling ◽  
Cell Receptor Signaling

Abstract Abstract 1045 In patients with FLT3-ITD mutated AML, FLT3-inhibitors have been used successfully as a ‘bridging therapy’ before allogeneic transplantation. Inhibitors of other kinases (such as imatinib for BCR-ABL positive CML) have previously been used successfully after allogeneic transplantation – even before discontinuation of immunosuppressive medication. However, it is known that some BCR-ABL inhibitors such as dasatinib exert strong inhibitory effects on primary T-cells through inhibition of Src-kinases relevant for T-cell receptor signaling. Even imatinib and nilotinib - although not affecting Src kinase activity – showed decreased T-cell activation and reactivity to some extent. Thus, the influence of FLT3-kinase inhibitors on T-cell function may be critical in the context of allogeneic bone marrow transplantation for FLT3-ITD-positive AML. Besides inhibition of FLT3-kinase, midostaurin (PKC412) exerts activity against PDGFR, VEGFR or c-KIT. In contrast, second generation inhibitors such as quizartinib (AC220) act in a far more FLT3-specific manner. Therefore, we aimed to investigate the effects of both clinically relevant FLT3-inhibitors on T-cell receptor signaling in comparison to the well characterized and potent BCR-ABL inhibitor dasatinib. Investigating primary T-cells derived from healthy donors, we applied a dose range of 10–50 nM dasatinib, 5–50nM midostaurin and 10–50 nM quizartinib. These dose ranges have been previously described to be achievable as trough levels during inhibitor therapy in early clinical trials. Upon incubation with dasatinib (10nM and 50nM), we found overall reduction in global tyrosine phosphorylation as detected by Western-blotting using the 4G10 antibody. In contrast, treatment with midostaurin left the activation of T-cell receptor signaling pathways unaffected. Comparable to DMSO control, overall phosphorylation was induced almost immediately after stimulation. Western-blotting of LCK and Plcg1 showed similar time dependent activation compared to total phosphorylation. Likewise, quizartinib did not reduce overall tyrosine phosphorylation level and left activation of downstream kinases (ZAP70, MAPK, LCK, Plcg1) largely unaffected. As activation of primary T-cells is a critical step in immune responses against viral and tumor antigens we aimed to investigate the influence of FLT3-kinase inhibitors quizartinib and midostaurin on activation of CD8+ T-cells. T-cells from healthy donors were stimulated using either PHA 0.5% or CD3/CD28 beads to ensure a more T-cell receptor specific stimulation. Using CD3/CD28 stimulation, CD69 expression was almost abrogated following dasatinib treatment. Applying clinically relevant doses of midostaurin or quizartinib to isolated T-cells did not influence CD69 expression. Expression levels upon PHA or CD3/CD28 stimulation were comparable to DMSO-control - even in the presence of 50nM midostaurin or quizartinib. Proliferation of T-cells upon CD3/CD28 stimulation was impaired by dasatinib treatment, while midostaurin and quizartinib left T-cell proliferation largely unaffected – as determined by CSFE staining. In order to investigate the T cell allo-reactivity, mixed lymphocyte culture was performed, where human pan-T-cells are co-cultured with allogeneic antigen presenting cells. T-cell proliferation – as measured by 3H-thymidine incorporation – was significantly impaired by dasatanib but neither midostaurin nor quizartinib treatment. Investigation of leukemia- and virus-antigen-specific T-cell responses are currently under way to gain deeper insight regarding this clinically relevant scenario. Overall, we found FLT3-kinase inhibitors midostaurin and quizartinib to leave T-cell activation, proliferation and function unaffected in-vitro. This information may be useful for the design of up-coming clinical trials testing the safety and efficacy of FLT3-kinase inhibitors in combination with allogeneic stem-cell transplantation. Disclosures: Lipka: Novartis Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Heidel:Novartis Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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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