scholarly journals CD28 costimulatory signal induces protein arginine methylation in T cells

2005 ◽  
Vol 202 (3) ◽  
pp. 371-377 ◽  
Author(s):  
Fabien Blanchet ◽  
Ana Cardona ◽  
Fabrice A. Letimier ◽  
Michael S. Hershfield ◽  
Oreste Acuto
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Posttranslational Modifications ◽  
Cell Activation ◽  
Lymphocyte Activation ◽  
Arginine Methylation ◽  
Methyltransferase Activity ◽  
Arginine Methyltransferase ◽  
Protein Arginine Methylation ◽  
Human And Mouse

Protein phosphorylation initiates signal transduction that triggers lymphocyte activation. However, other posttranslational modifications may contribute to this process. Here, we show that CD28 engagement induced protein arginine methyltransferase activity and methylation on arginine of several proteins, including Vav1. Methylation of Vav1 and IL-2 production were reduced by inhibiting S-adenosyl-L-homocysteine hydrolase, an enzyme that regulates cellular transmethylation. Methylated Vav1 was induced in human and mouse T cells and selectively localized in the nucleus, which suggested that this form marks a nuclear function of Vav1. Our findings uncover a signaling pathway that is controlled by CD28 that is likely to be important for T cell activation.

scholarly journals Arginine methylation regulates IL-2 gene expression: a role for protein arginine methyltransferase 5 (PRMT5)

2005 ◽  
Vol 388 (1) ◽  
pp. 379-386 ◽  
Author(s):  
Stéphane RICHARD ◽  
Mélanie MOREL ◽  
Patrick CLÉROUX
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Arginine Methylation ◽  
Cytokine Gene Expression ◽  
Luciferase Reporter ◽  
Protein Arginine Methylation

Arginine methylation is a post-translational modification resulting in the generation of aDMAs (asymmetrical ω-NG, NG-dimethylated arginines) and sDMAs (symmetrical ω-NG, N′G-dimethylated arginines). The role of arginine methylation in cell signalling and gene expression in T lymphocytes is not understood. In the present study, we report a role for protein arginine methylation in regulating IL-2 (interleukin 2) gene expression in T lymphocytes. Leukaemic Jurkat T-cells treated with a known methylase inhibitor, 5′-methylthioadenosine, had decreased cytokine gene expression, as measured using an NF-AT (nuclear factor of activated T-cells)-responsive promoter linked to the luciferase reporter gene. Since methylase inhibitors block all methylation events, we performed RNA interference with small interfering RNAs against the major PRMT (protein arginine methyltransferases) that generates sDMA (PRMT5). The dose-dependent decrease in PRMT5 expression resulted in the inhibition of both IL-2- and NF-AT-driven promoter activities and IL-2 secretion. By using an sDMA-specific antibody, we observed that sDMA-containing proteins are directly associated with the IL-2 promoter after T-cell activation. Since changes in protein arginine methylation were not observed after T-cell activation in Jurkat and human peripheral blood lymphocytes, our results demonstrate that it is the recruitment of methylarginine-specific protein(s) to cytokine promoter regions that regulates their gene expression.

scholarly journals Role of Ly-6 in lymphocyte activation. II. Induction of T cell activation by monoclonal anti-Ly-6 antibodies.

1986 ◽  
Vol 164 (3) ◽  
pp. 709-722 ◽  
Author(s):  
T R Malek ◽  
G Ortega ◽  
C Chan ◽  
R A Kroczek ◽  
E M Shevach
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Proliferative Response ◽  
Cell Activation ◽  
Critical Role ◽  
Lymphocyte Activation ◽  
Accessory Cells ◽  
Peripheral T Cells ◽  
Activation Cascade

The Ly-6 locus controls the expression and/or encodes for alloantigenic specificities found primarily on subpopulations of murine T and B lymphocytes. We have recently identified and characterized a new rat mAb, D7, that recognizes a nonpolymorphic Ly-6 specificity. After crosslinking by anti-Ig reagents or by Fc receptor-bearing accessory cells, mAb D7 could induce IL-2 production from T cell hybridomas, and in the presence of PMA could trigger a vigorous proliferative response in resting peripheral T cells. The addition of mAb D7 to cultures of antigen- and alloantigen-, but not mitogen-stimulated T cells resulted in a marked augmentation of the proliferative response. A number of other well-characterized mAbs to Ly-6 locus products could also stimulate a T cell proliferative response after crosslinking by anti-Ig and in the presence of PMA. These results strongly suggest that Ly-6 molecules may play a critical role in the T cell activation cascade, either as receptors for an unidentified soluble or cell-associated ligand or as transducing molecules that modulate signals initiated by antigen stimulation of the T3-Ti complex.

scholarly journals Shikonin Suppresses Human T Lymphocyte Activation through Inhibition of IKKβActivity and JNK Phosphorylation

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Ting Li ◽  
Fenggen Yan ◽  
Rui Wang ◽  
Hua Zhou ◽  
Liang Liu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Nuclear Translocation ◽  
Lymphocyte Activation ◽  
Immunosuppressive Agent ◽  
Buffy Coat ◽  
T Lymphocyte Activation

The key role of T cells has been elaborated in mediating immune responses and pathogenesis of human inflammatory and autoimmune conditions. In the current study the effect of shikonin, a compound isolated from a medicinal plant, on inhibition of T-cell activation was firstly examined by using primary human T lymphocytes isolated from buffy coat. Results showed that shikonin dose dependently suppressed T-cell proliferation, IL-2 and IFN-γsecretion, CD69 and CD25 expression, as well as cell cycle arrest activated by costimulation of PMA/ionomycin or OKT-3/CD28 monoclonal antibodies. Moreover, these inhibitory responses mediated by shikonin were found to be associated with suppression of the NF-κB signaling pathway via inhibition of the IKKα/βphosphorylation, IκB-αphosphorylation and degradation, and NF-κB nuclear translocation by directly decreasing IKKβactivity. Moreover, shikonin suppressed JNK phosphorylation in the MAPKs pathway of T cells. In this connection, we conclude that shikonin could suppress T lymphocyte activation through suppressing IKKβactivity and JNK signaling, which suggests that shikonin is valuable for further investigation as a potential immunosuppressive agent.

Human T Lymphocyte Activation Kinetics for Identifying and Targeting Alloreactive T Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5249-5249
Author(s):  
Rajinder P.S. Bajwa ◽  
Philip L. McCarthy ◽  
Paul K. Wallace ◽  
Stephen Wallace ◽  
Yiyuan Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Lymphocyte Activation ◽  
Activation Kinetics ◽  
Cd25 Expression ◽  
Alloreactive T Cells ◽  
Selective Depletion

Abstract Selective depletion of alloreactive T cells from a stem cell graft has the potential of reducing graft versus host disease (GvHD) while preserving graft versus malignancy and third party responses. For this purpose several techniques generate and deplete alloreactive cells, which are donor-derived T cells activated by recipient tissue. The kinetics of T cell activation in donor-recipient co-culture systems is critical in optimizing the timing of depletion of alloreactive T cells. We present the T cell activation kinetics in our preclinical system. Peripheral blood mononuclear cells (PBMCs) were derived from several pairs of unrelated healthy human volunteers. 2500 cGy irradiated cells (stimulators) were co-cultured with PBMCs (responders) in a 1:1 ratio and a concentration of 5 x 106/ml in serum free medium. Stimulator cells were labeled with PKH67 and the co-cultures were, analyzed for CD3, CD4, and CD25, expression by flow cytometry on days 0 through 7, using Topro-3 to exclude dead cells. We also added low dose Interleukin-2 (IL2) for augmenting the generation of alloreactive cells, to see if this made a difference. Our results show that alloreactive CD8 cells (CD3+, CD4−, CD25+) increased from ≤1 % on day 0, to 6.5 percent by day 5; the addition of IL2 amplified this to nearly 10% by day 5. CD4 + activated T cells (CD3+, CD4+, CD25+dim or total) did not appreciably increase over time and ranged between 2 to 5%; the addition of IL2 did not have any effect. T regulatory cells (CD3+, CD4+, CD25+bright) increased from ≤1 percent at baseline to 5% by day 5 and these were unaffected by the addition of IL2. The proportion of non-activated T lymphocytes, decreased with time of co-culture progression. Our results show that T lymphocyte activation, defined by CD25 expression, progressively increases through the first week of co-culture. This important observation will help in establishing the timing of allograft manipulation, for the selective depletion of alloreactive T cells in clinical hematopoietic stem cell transplantation. Figure Figure

scholarly journals Discs large (Dlg1) complexes in lymphocyte activation

2004 ◽  
Vol 166 (2) ◽  
pp. 173-178 ◽  
Author(s):  
Ramnik Xavier ◽  
Shahrooz Rabizadeh ◽  
Kazuhiro Ishiguro ◽  
Niko Andre ◽  
J. Bernabe Ortiz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Pdz Domain ◽  
Lymphocyte Activation ◽  
Cortical Actin ◽  
Signaling Complex ◽  
Discs Large ◽  
Nfat Activation

T cell antigen recognition involves the formation of a structured interface between antigen-presenting and T cells that facilitates the specific transmission of activating and desensitizing stimuli. The molecular machinery that organizes the signaling molecules and controls their disposition in response to activation remains poorly understood. We show here that in T cells Discs large (Dlg1), a PDZ domain-containing protein, is recruited upon activation to cortical actin and forms complexes with early participants in T cell activation. Transient overexpression of Dlg1 attenuates basal and Vav1-induced NFAT reporter activation. Reduction of Dlg1 expression by RNA interference enhances both CD3- and superantigen-mediated NFAT activation. Attenuation of antigen receptor signaling appears to be a complex, highly orchestrated event that involves the mutual segregation of important elements of the early signaling complex.

scholarly journals C-terminal modification of the insulin B:11–23 peptide creates superagonists in mouse and human type 1 diabetes

2017 ◽  
Vol 115 (1) ◽  
pp. 162-167 ◽  
Author(s):  
Yang Wang ◽  
Tomasz Sosinowski ◽  
Andrey Novikov ◽  
Frances Crawford ◽  
David B. Neau ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell Activation ◽  
Posttranslational Modifications ◽  
Cell Activation ◽  
Nod Mice ◽  
Side Chain ◽  
C Terminus

A polymorphism at β57 in some major histocompatibility complex class II (MHCII) alleles of rodents and humans is associated with a high risk for developing type 1 diabetes (T1D). However, a highly diabetogenic insulin B chain epitope within the B:9–23 peptide is presented poorly by these alleles to a variety of mouse and human CD4 T cells isolated from either nonobese diabetic (NOD) mice or humans with T1D. We have shown for both species that mutations at the C-terminal end of this epitope dramatically improve presentation to these T cells. Here we present the crystal structures of these mutated peptides bound to mouse IAg7 and human HLA-DQ8 that show how the mutations function to improve T-cell activation. In both peptide binding grooves, the mutation of B:22R to E in the peptide changes a highly unfavorable side chain for the p9 pocket to an optimal one that is dependent on the β57 polymorphism, accounting for why these peptides bind much better to these MHCIIs. Furthermore, a second mutation of the adjacent B:21 (E to G) removes a side chain from the surface of the complex that is highly unfavorable for a subset of NOD mouse CD4 cells, thereby greatly enhancing their response to the complex. These results point out the similarities between the mouse and human responses to this B chain epitope in T1D and suggest there may be common posttranslational modifications at the C terminus of the peptide in vivo to create the pathogenic epitopes in both species.

scholarly journals Antitumor Effect of KML-B-Treated Dendritic Cells via Induction of Lymphocyte Activation

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Jong-Jin Kim ◽  
Yun-Ho Hwang ◽  
Kyung-Yun Kang ◽  
Sung-Ju Lee ◽  
Jong-Bae Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antitumor Effect ◽  
Biological Activities ◽  
Lymphocyte Activation ◽  
Carbohydrate Binding ◽  
Mistletoe Lectin

Lectins are carbohydrate-binding proteins with various biological activities, such as antitumor and immunomodulatory effects. Although lectins have various biological activities, they are still limited by cytotoxicity in normal cells. To overcome this problem, we used the noncytotoxic part of Korean mistletoe lectin B-chain (KML-B) to induce maturation of dendritic cells (DCs). A previous study reported that KML-B induces DC maturation by triggering TLR-4, including expression of costimulatory molecules (CD40, CD80, and CD86), MHC II, and secretion of cytokines in DCs. Additionally, matured DCs by KML-B induced T helper (Th) cell activation and differentiation toward Th1 cells. However, the interaction of KML-B-treated DCs with CD8+ T cells is still poorly understood. In this study, we confirmed the ability of matured DCs by KML-B to stimulate cytotoxic T cells using OT-1 mouse-derived CD8+ T cells. KML-B induced MHC I expression in DCs, stimulation of CD8+ T cell activation and proliferation, and IFN-γ secretion. Moreover, tumor sizes were reduced by KML-B treatment during vaccination of OVA257−264-pulsed DCs. Here, we confirmed induction of CD8+ T cell activation and the antitumor effect of KML-B treatment in DCs.

scholarly journals Deep Immune Profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19

2020 ◽  
Author(s):  
Laura A. Vella ◽  
Josephine R. Giles ◽  
Amy E. Baxter ◽  
Derek A. Oldridge ◽  
Caroline Diorio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Cell Activation ◽  
Vascular Complications ◽  
Lymphocyte Activation ◽  
Adult Disease ◽  
Vasoactive Medication

ABSTRACTPediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8 T cells that correlated with use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct and implicate CD8 T cells in clinical presentation and trajectory of MIS-C.One Sentence SummaryMIS-C is defined by generalized lymphocyte activation that corrects during hospitalization, including elevated plasmablast frequencies and marked activation of vascular patrolling CX3CR1+ CD8 T cells.

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