scholarly journals SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity

Science ◽  
2021 ◽  
Vol 372 (6543) ◽  
pp. eaba4220 ◽  
Author(s):  
Tao Yue ◽  
Xiaoming Zhan ◽  
Duanwu Zhang ◽  
Ruchi Jain ◽  
Kuan-wen Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Cell Mediated Immunity ◽  
Activated T Cells ◽  
Granule Formation

Reactive oxygen species (ROS) increase in activated T cells because of metabolic activity induced to support T cell proliferation and differentiation. We show that these ROS trigger an oxidative stress response that leads to translation repression. This response is countered by Schlafen 2 (SLFN2), which directly binds transfer RNAs (tRNAs) to protect them from cleavage by the ribonuclease angiogenin. T cell–specific SLFN2 deficiency results in the accumulation of tRNA fragments, which inhibit translation and promote stress-granule formation. Interleukin-2 receptor β (IL-2Rβ) and IL-2Rγ fail to be translationally up-regulated after T cell receptor stimulation, rendering SLFN2-deficient T cells insensitive to interleukin-2’s mitogenic effects. SLFN2 confers resistance against the ROS-mediated translation-inhibitory effects of oxidative stress normally induced by T cell activation, permitting the robust protein synthesis necessary for T cell expansion and immunity.

Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2181-2190 ◽  
Author(s):  
Maria Paola Martelli ◽  
Huamao Lin ◽  
Weiguo Zhang ◽  
Lawrence E. Samelson ◽  
Barbara E. Bierer
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Adapter Protein ◽  
Activated T Cells

Abstract Activation of T cells can be initiated through cell surface molecules in addition to the T-cell receptor-CD3 (TCR-CD3) complex. In human T cells, ligation of the CD2 molecule by mitogenic pairs of anti-CD2 monoclonal antibodies activates T cells via biochemical signaling pathways similar but not identical to those elicited on TCR engagement. This study describes a key role for the p36/38 membrane adapter protein linker for T cell activation (LAT) in CD2-mediated T-cell activation. Following ligation of CD2 on the surface of the Jurkat T-cell line and human purified T cells, LAT was tyrosine phosphorylated and shown to associate in vivo with a number of other tyrosine phosphorylated proteins including PLCγ-1, Grb-2, and SLP-76. Using Jurkat cell lines deficient in ZAP70/Syk (P116) or LAT (ANJ3) expression, CD2-dependent PLCγ-1 and SLP-76 tyrosine phosphorylation required expression both of ZAP70 or Syk and of LAT. As predicted, the absence of either LAT or ZAP70/Syk kinases correlated with a defect in the induction of nuclear factor of activated T cells (NFAT) transcriptional activity, activation of the interleukin-2 promoter, and ERK phosphorylation following CD2 stimulation. These data suggest that LAT is an adapter protein important for the regulation of CD2-mediated T-cell activation.

Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2181-2190 ◽  
Author(s):  
Maria Paola Martelli ◽  
Huamao Lin ◽  
Weiguo Zhang ◽  
Lawrence E. Samelson ◽  
Barbara E. Bierer
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Adapter Protein ◽  
Activated T Cells

Activation of T cells can be initiated through cell surface molecules in addition to the T-cell receptor-CD3 (TCR-CD3) complex. In human T cells, ligation of the CD2 molecule by mitogenic pairs of anti-CD2 monoclonal antibodies activates T cells via biochemical signaling pathways similar but not identical to those elicited on TCR engagement. This study describes a key role for the p36/38 membrane adapter protein linker for T cell activation (LAT) in CD2-mediated T-cell activation. Following ligation of CD2 on the surface of the Jurkat T-cell line and human purified T cells, LAT was tyrosine phosphorylated and shown to associate in vivo with a number of other tyrosine phosphorylated proteins including PLCγ-1, Grb-2, and SLP-76. Using Jurkat cell lines deficient in ZAP70/Syk (P116) or LAT (ANJ3) expression, CD2-dependent PLCγ-1 and SLP-76 tyrosine phosphorylation required expression both of ZAP70 or Syk and of LAT. As predicted, the absence of either LAT or ZAP70/Syk kinases correlated with a defect in the induction of nuclear factor of activated T cells (NFAT) transcriptional activity, activation of the interleukin-2 promoter, and ERK phosphorylation following CD2 stimulation. These data suggest that LAT is an adapter protein important for the regulation of CD2-mediated T-cell activation.

scholarly journals CD28-B7 interactions allow the induction of CD8+ cytotoxic T lymphocytes in the absence of exogenous help.

1993 ◽  
Vol 177 (6) ◽  
pp. 1791-1796 ◽  
Author(s):  
F A Harding ◽  
J P Allison
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Histocompatibility Complex ◽  
Necessary And Sufficient ◽  
Additional Antigen

The activation requirements for the generation of CD8+ cytotoxic T cells (CTL) are poorly understood. Here we demonstrate that in the absence of exogenous help, a CD28-B7 interaction is necessary and sufficient for generation of class I major histocompatibility complex-specific CTL. Costimulation is required only during the inductive phase of the response, and not during the effector phase. Transfection of the CD28 counter receptor, B7, into nonstimulatory P815 cells confers the ability to elicit P815-specific CTL, and this response can be inhibited by anti-CD28 Fab or by the chimeric B7-binding protein CTLA4Ig. Anti-CD28 monoclonal antibody (mAb) can provide a costimulatory signal to CD8+ T cells when the costimulatory capacity of splenic stimulators is destroyed by chemical fixation. CD28-mediated signaling provokes the release of interleukin 2 (IL-2) from the CD8+ CTL precursors, as anti-CD28 mAb could be substituted for by the addition of IL-2, and an anti-IL-2 mAb can block the generation of anti-CD28-induced CTL. CD4+ cells are not involved in the costimulatory response in the systems examined. We conclude that CD8+ T cell activation requires two signals: an antigen-specific signal mediated by the T cell receptor, and an additional antigen nonspecific signal provided via a CD28-B7 interaction.

T cells: a dedicated effector kinase pathways for every trait?

2021 ◽  
Vol 478 (6) ◽  
pp. 1303-1307
Author(s):  
Kriti Bahl ◽  
Jeroen P. Roose
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Spectrometric Analysis ◽  
Activated T Cells ◽  
Biological Responses ◽  
Extracellular Signal ◽  
Differentiation And Proliferation

Signaling pathways play critical roles in regulating the activation of T cells. Recognition of foreign peptide presented by MHC to the T cell receptor (TCR) triggers a signaling cascade of proximal kinases and adapter molecules that lead to the activation of Effector kinase pathways. These effector kinase pathways play pivotal roles in T cell activation, differentiation, and proliferation. RNA sequencing-based methods have provided insights into the gene expression programs that support the above-mentioned cell biological responses. The proteome is often overlooked. A recent study by Damasio et al. [Biochem. J. (2021) 478, 79–98. doi:10.1042/BCJ20200661] focuses on characterizing the effect of extracellular signal-regulated kinase (ERK) on the remodeling of the proteome of activated CD8+ T cells using Mass spectrometric analysis. Surprisingly, the Effector kinase ERK pathway is responsible for only a select proportion of the proteome that restructures during T cell activation. The primary targets of ERK signaling are transcription factors, cytokines, and cytokine receptors. In this commentary, we discuss the recent findings by Damasio et al. [Biochem. J. (2021) 478, 79–98. doi:10.1042/BCJ20200661] in the context of different Effector kinase pathways in activated T cells.

Effect of CD28 signal transduction on c-Rel in human peripheral blood T cells

1994 ◽  
Vol 14 (12) ◽  
pp. 7933-7942
Author(s):  
R G Bryan ◽  
Y Li ◽  
J H Lai ◽  
M Van ◽  
N R Rice ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Nuclear Translocation ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Cd28 Costimulation

Optimal T-cell activation requires both an antigen-specific signal delivered through the T-cell receptor and a costimulatory signal which can be delivered through the CD28 molecule. CD28 costimulation induces the expression of multiple lymphokines, including interleukin 2 (IL-2). Because the c-Rel transcription factor bound to and activated the CD28 response element within the IL-2 promoter, we focused our study on the mechanism of CD28-mediated regulation of c-Rel in human peripheral blood T cells. We showed that CD28 costimulation accelerated the kinetics of nuclear translocation of c-Rel (and its phosphorylated form), p50 (NFKB1), and p65 (RelA). The enhanced nuclear translocation of c-Rel correlated with the stimulation of Il-2 production and T-cell proliferation by several distinct anti-CD28 monoclonal antibodies. This is explained at least in part by the long-term downregulation of I kappa B alpha following CD28 signalling as opposed to phorbol myristate acetate alone. Furthermore, we showed that the c-Rel-containing CD28-responsive complex is enhanced by, but not specific to, CD28 costimulation. Our results indicate that c-Rel is one of the transcription factors targeted by CD28 signalling.

scholarly journals Unc119, a Novel Activator of Lck/Fyn, Is Essential for T Cell Activation

2004 ◽  
Vol 199 (3) ◽  
pp. 369-379 ◽  
Author(s):  
Magdalena M. Gorska ◽  
Susan J. Stafford ◽  
Osman Cen ◽  
Sanjiv Sur ◽  
Rafeul Alam
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cellular Proliferation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
The Novel ◽  
Tcr Signaling ◽  
Src Homology

The first step in T cell receptor for antigen (TCR) signaling is the activation of the receptor-bound Src kinases, Lck and Fyn. The exact mechanism of this process is unknown. Here, we report that the novel Src homology (SH) 3/SH2 ligand–Uncoordinated 119 (Unc119) associates with CD3 and CD4, and activates Lck and Fyn. Unc119 overexpression increases Lck/Fyn activity in T cells. In Unc119-deficient T cells, Lck/Fyn activity is dramatically reduced with concomitant decrease in interleukin 2 production and cellular proliferation. Reconstitution of cells with Unc119 reverses the signaling and functional outcome. Thus, Unc119 is a receptor-associated activator of Src-type kinases. It provides a novel mechanism of signal generation in the TCR complex.

scholarly journals Pannexin-1 hemichannel–mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse

Blood ◽  
2010 ◽  
Vol 116 (18) ◽  
pp. 3475-3484 ◽  
Author(s):  
Tobias Woehrle ◽  
Linda Yip ◽  
Abdallah Elkhal ◽  
Yuka Sumi ◽  
Yu Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Atp Release ◽  
Activated T Cells ◽  
Immune Synapse ◽  
Pannexin 1 ◽  
P2x4 Receptors

Abstract Engagement of T cells with antigen-presenting cells requires T-cell receptor (TCR) stimulation at the immune synapse. We previously reported that TCR stimulation induces the release of cellular adenosine-5′-triphosphate (ATP) that regulates T-cell activation. Here we tested the roles of pannexin-1 hemichannels, which have been implicated in ATP release, and of various P2X receptors, which serve as ATP-gated Ca2+ channels, in events that control T-cell activation. TCR stimulation results in the translocation of P2X1 and P2X4 receptors and pannexin-1 hemichannels to the immune synapse, while P2X7 receptors remain uniformly distributed on the cell surface. Removal of extracellular ATP or inhibition, mutation, or silencing of P2X1 and P2X4 receptors inhibits Ca2+ entry, nuclear factors of activated T cells (NFAT) activation, and induction of interleukin-2 synthesis. Inhibition of pannexin-1 hemichannels suppresses TCR-induced ATP release, Ca2+ entry, and T-cell activation. We conclude that pannexin-1 hemichannels and P2X1 and P2X4 receptors facilitate ATP release and autocrine feedback mechanisms that control Ca2+ entry and T-cell activa-tion at the immune synapse.

Shedded neuronal ICAM-5 suppresses T-cell activation

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3615-3625 ◽  
Author(s):  
Li Tian ◽  
Jani Lappalainen ◽  
Matti Autero ◽  
Satu Hänninen ◽  
Heikki Rauvala ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Soluble Form ◽  
Mammalian Brain ◽  
Activated T Cells ◽  
Activation Markers ◽  
Costimulatory Signals

Abstract Intercellular adhesion molecules (ICAMs) bind to leukocyte β2 integrins, which, among other functions, provide costimulatory signals for T-cell activation. ICAM-5 (telencephalin) is expressed in the somadendritic region of neurons of the mammalian brain. The receptor for ICAM-5 is the integrin LFA-1, a major leukocyte integ-rin expressed in lymphocytes and microglia. In conditions of brain ischemia, epilepsy, and encephalitis, the soluble form of ICAM-5 (sICAM-5) has been detected in physiologic fluids. Here, we report that sICAM-5 attenuates the T-cell receptor-mediated activation of T cells as demonstrated by the decreased expression of the activation markers CD69, CD40L, and CD25 (IL-2R). This effect is most clearly seen in CD45ROLow (naive), and not in CD45ROHigh (memory) T cells, and is most effective early in priming, but not in the presence of strong costimulatory signals. Furthermore, sICAM-5 promotes the mRNA expression of the cytokines TGF-β1 and IFN-γ, but not TNF. The formation of sICAM-5 is promoted by activated T cells through the cleavage of ICAM-5 from neurons. This suggests that ICAM-5 is involved in immune privilege of the brain and acts as an anti-inflammatory agent.

scholarly journals The Ca2+-activated K+ channel KCa3.1 compartmentalizes in the immunological synapse of human T lymphocytes

2007 ◽  
Vol 292 (4) ◽  
pp. C1431-C1439 ◽  
Author(s):  
Stella A. Nicolaou ◽  
Lisa Neumeier ◽  
YouQing Peng ◽  
Daniel C. Devor ◽  
Laura Conforti
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
K Channel ◽  
Activated T Cells ◽  
Barr Virus

T cell receptor engagement results in the reorganization of intracellular and membrane proteins at the T cell-antigen presenting cell interface forming the immunological synapse (IS), an event required for Ca2+ influx. KCa3.1 channels modulate Ca2+ signaling in activated T cells by regulating the membrane potential. Nothing is known regarding KCa3.1 membrane distribution during T cell activation. Herein, we determined whether KCa3.1 translocates to the IS in human T cells using YFP-tagged KCa3.1 channels. These channels showed electrophysiological and pharmacological properties identical to wild-type channels. IS formation was induced by either anti-CD3/CD28 antibody-coated beads for fixed microscopy experiments or Epstein-Barr virus-infected B cells for fixed and live cell microscopy. In fixed microscopy experiments, T cells were also immunolabeled for F-actin or CD3ε, which served as IS formation markers. The distribution of KCa3.1 was determined with confocal and fluorescence microscopy. We found that, upon T cell activation, KCa3.1 channels localize with F-actin and CD3ε to the IS but remain evenly distributed on the cell membrane when no stimulus is provided. Detailed imaging experiments indicated that KCa3.1 channels are recruited in the IS shortly after antigen presentation and are maintained there for at least 15–30 min. Interestingly, pretreatment of activated T cells with the specific KCa3.1 blocker TRAM-34 blocked Ca2+ influx, but channel redistribution to the IS was not prevented. These results indicate that KCa3.1 channels are a part of the signaling complex that forms at the IS upon antigen presentation.

scholarly journals p21ras and calcineurin synergize to regulate the nuclear factor of activated T cells.

1993 ◽  
Vol 178 (5) ◽  
pp. 1517-1522 ◽  
Author(s):  
M Woodrow ◽  
N A Clipstone ◽  
D Cantrell
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Protein Tyrosine Kinase ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cytosolic Calcium ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Guanine Nucleotide Binding Protein

In T lymphocytes, triggering of the T cell receptor (TCR) induces several signaling cascades which ultimately synergize to induce the activity of the nuclear factor of activated T cells (NFAT), a DNA binding complex critical to the inducibility and T cell specificity of the T cell growth factor interleukin 2. One immediate consequence of T cell activation via the TCR is an increase in cytosolic calcium. Calcium signals are important for NFAT induction, and recent studies have identified calcineurin, a calcium-calmodulin dependent serine-threonine phosphatase, as a prominent component of the calcium signaling pathway in T cells. A second important molecule in TCR signal transduction is the guanine nucleotide binding protein, p21ras, which is coupled to the TCR by a protein tyrosine kinase dependent mechanism. The experiments presented here show that expression by transfection of mutationally activated calcineurin or activated p21ras alone is insufficient for NFAT transactivation. However, coexpression of the activated calcineurin with activated p21ras could mimic TCR signals in NFAT induction. These data identify calcineurin and p21ras as cooperative partners in T cell activation.

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