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.

scholarly journals DC-HIL is a negative regulator of T lymphocyte activation

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4320-4327 ◽  
Author(s):  
Jin-Sung Chung ◽  
Kota Sato ◽  
Irene I. Dougherty ◽  
Ponciano D. Cruz ◽  
Kiyoshi Ariizumi
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Lymphocyte Activation ◽  
Negative Regulator ◽  
Secondary Response ◽  
Inhibitory Function ◽  
T Lymphocyte Activation

Abstract T-cell activation is the net product of competing positive and negative signals transduced by regulatory molecules on antigen-presenting cells (APCs) binding to corresponding ligands on T cells. Having previously identified DC-HIL as a receptor expressed by APCs that contains an extracellular immunoglobulin (Ig)–like domain, we postulated that it plays a role in T-cell activation. To probe this function, we created soluble recombinant DC-HIL, which we observed to bind activated (but not resting) T cells, indicating that expression of the putative ligand on T cells is induced by activation. Binding of DC-HIL to naive T cells attenuated these cells' primary response to anti-CD3 antibody, curtailing IL-2 production, and preventing entry into the cell cycle. DC-HIL also inhibited reactivation of T cells previously activated by APCs (secondary response). By contrast, addition of soluble DC-HIL to either allogeneic or ovalbumin-specific lymphocyte reactions augmented T-cell proliferation, and its injection into mice during the elicitation (but not sensitization) phase of contact hypersensitivity exacerbated ear-swelling responses. Mutant analyses showed the inhibitory function of DC-HIL to reside in its extracellular Ig-like domain. We conclude that endogenous DC-HIL is a negative regulator of T lymphocyte activation, and that this native inhibitory function can be blocked by exogenous DC-HIL, leading to enhanced immune responses.

scholarly journals Systemic and Mucosal T-Lymphocyte Activation Induced by Recombinant Adenovirus Vaccines in Rhesus Monkeys

2009 ◽  
Vol 83 (20) ◽  
pp. 10596-10604 ◽  
Author(s):  
Yue Sun ◽  
Robert T. Bailer ◽  
Srinivas S. Rao ◽  
John R. Mascola ◽  
Gary J. Nabel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Rhesus Monkeys ◽  
Recombinant Adenovirus ◽  
Lymphocyte Activation ◽  
T Cell Responses ◽  
Cell Responses ◽  
T Lymphocyte Activation

ABSTRACT The administration of vectors designed to elicited cell-mediated immune responses may have other consequences that are clinically significant. To explore this possibility, we evaluated T-cell activation during the first 2 months after recombinant adenovirus serotype 5 (rAd5) prime or boost immunizations in rhesus monkeys. We also evaluated the kinetics of T-lymphocyte activation in both the systemic and the mucosal compartments after rAd5 administration in monkeys with preexisting immunity to Ad5. The rAd5 immunization induced lower-frequency Gag epitope-specific CD8+ T cells in the colonic mucosa than in the peripheral blood. There was evidence of an expansion of the simian immunodeficiency virus Gag-specific CD8+ T-cell responses, but not the Ad5 hexon-specific T-cell responses, following a homologous rAd5 boost. A striking but transient T-lymphocyte activation in both the systemic and the mucosal compartments of rhesus monkeys was observed after rAd5 immunization. These findings indicate that the administration of a vaccine vector such as Ad5 can induce a global activation of T cells.

scholarly journals Causes of T lymphocyte activation in HIV-infected patients coinfected with hepatitis C virus

2016 ◽  
Vol 88 (11) ◽  
pp. 22-28
Author(s):  
K V Shmagel ◽  
N G Shmagel ◽  
L B Korolevskaya ◽  
E V Saydakova ◽  
V A Chereshnev
Keyword(s):  
T Cells ◽  
Hepatitis C ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Lymphocyte Activation ◽  
Cd8 T Cell ◽  
Cd8 T Lymphocytes

Aim. To establish the causes of T lymphocyte activation in human immunodeficiency virus (HIV)-infected patients coinfected with hepatitis C (HCV) who are adherent to their antiretroviral therapy regimen and interferon untreated. Subjects and methods. Examinations were made in 62 people who were HIV+HCV-positive (n=21), HIV+HCV-negative (n=21), and noninfected volunteers (n=20). The activation (CD38+HLA-DR+) and proliferation (Ki-67+) of CD4+ and CD8+ T lymphocytes were estimated. The blood concentration of intestinal fatty acid-binding protein (I-FABP) was determined. Results. The proportion of activated cells among the CD4+ T lymphocytes was equal in the HIV+HCV-positive and HIV+HCV-negative groups. But these indicators were statistically significantly higher than those in the controls (HIV- HCV-). CD8+ T cell activation was greater in the HIV/HCV-coinfected patients than that in the other groups and that was higher in the HIV monoinfected than in the noninfected. The blood I-FABP concentrations were elevated in the HIV+HCV-positive and HIV+HCV groups compared with those in the HIV-HCV-negative group, but these did not differ among themselves. In the HIV+HCV-negative patients, CD4+ and CD8+ T cell activation directly and statistically significantly correlated with blood I-FABP levels. In the HIV+HCV-positive group, this correlation remained only for CD4+ T lymphocytes. CD8+ T cell activation in HIV/HCV-coinfected patients was unrelated to I-FABP concentrations. Conclusion. The increased activation of CD4+ and CD8+ T lymphocytes in HIV monoinfection was found to be associated with intestinal epithelial destruction and unrelated to cell division processes. In HIV/HCV coinfection, the activated state of CD4+ T cells is determined by both the level of proliferative processes and impairment of the intestinal barrier and that of CD8+ T cells is only by proliferation.

scholarly journals Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation.

1993 ◽  
Vol 177 (3) ◽  
pp. 637-645 ◽  
Author(s):  
C S Lin ◽  
R C Boltz ◽  
J T Blake ◽  
M Nguyen ◽  
A Talento ◽  
...  
Keyword(s):  
T Cell ◽  
Potassium Channels ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Lymphocyte Activation ◽  
Voltage Gated ◽  
Lymphokine Production ◽  
T Lymphocyte Activation ◽  
Human T Lymphocyte

The role that potassium channels play in human T lymphocyte activation has been investigated by using specific potassium channel probes. Charybdotoxin (ChTX), a blocker of small conductance Ca(2+)-activated potassium channels (PK,Ca) and voltage-gated potassium channels (PK,V) that are present in human T cells, inhibits the activation of these cells. ChTX blocks T cell activation induced by signals (e.g., anti-CD2, anti-CD3, ionomycin) that elicit a rise in intracellular calcium ([Ca2+]i) by preventing the elevation of [Ca2+]i in a dose-dependent manner. However, ChTX has no effect on the activation pathways (e.g., anti-CD28, interleukin 2 [IL-2]) that are independent of a rise in [Ca2+]i. In the former case, both proliferative response and lymphokine production (IL-2 and interferon gamma) are inhibited by ChTX. The inhibitory effect of ChTX can be demonstrated when added simultaneously, or up to 4 h after the addition of the stimulants. Since ChTX inhibits both PK,Ca and PK,V, we investigated which channel is responsible for these immunosuppressive effects with the use of two other peptides, noxiustoxin (NxTX) and margatoxin (MgTX), which are specific for PK,V. These studies demonstrate that, similar to ChTX, both NxTX and MgTX inhibit lymphokine production and the rise in [Ca2+]i. Taken together, these data provide evidence that blockade of PK,V affects the Ca(2+)-dependent pathways involved in T lymphocyte proliferation and lymphokine production by diminishing the rise in [Ca2+]i that occurs upon T cell activation.

scholarly journals Rab6-dependent retrograde traffic of LAT controls immune synapse formation and T cell activation

2018 ◽  
Vol 215 (4) ◽  
pp. 1245-1265 ◽  
Author(s):  
Jean-Marie Carpier ◽  
Andres E. Zucchetti ◽  
Laurence Bataille ◽  
Stéphanie Dogniaux ◽  
Massiullah Shafaq-Zadah ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Lymphocyte Activation ◽  
Retrograde Transport ◽  
Small Gtpase ◽  
Immune Synapse ◽  
T Lymphocyte Activation ◽  
Retrograde Traffic

The adapter molecule linker for activation of T cells (LAT) orchestrates the formation of signalosomes upon T cell receptor (TCR) stimulation. LAT is present in different intracellular pools and is dynamically recruited to the immune synapse upon stimulation. However, the intracellular traffic of LAT and its function in T lymphocyte activation are ill defined. We show herein that LAT, once internalized, transits through the Golgi–trans-Golgi network (TGN), where it is repolarized to the immune synapse. This retrograde transport of LAT depends on the small GTPase Rab6 and the target soluble N-ethylmaleimide-sensitive factor attachment protein receptor (t-SNARE) Syntaxin-16, two regulators of the endosome-to-Golgi/TGN retrograde transport. We also show in vitro in Syntaxin-16– or Rab6-silenced human cells and in vivo in CD4+ T lymphocytes of the Rab6 knockout mouse that this retrograde traffic controls TCR stimulation. These results establish that the retrograde traffic of LAT from the plasma membrane to the Golgi-TGN controls the polarized delivery of LAT at the immune synapse and T lymphocyte activation.

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 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.

Targeting The T Cell Component Of The Tumour Microenvironment In Chronic Lymphocytic Leukaemia; A Potential Therapeutic Strategy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4147-4147
Author(s):  
Kirsty M Cuthill ◽  
Andrea Gail Sherman Buggins ◽  
Pj Chana ◽  
Stephen Devereux
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Lymphocytic Leukaemia ◽  
Nuclear Translocation ◽  
Tumour Microenvironment

Abstract It has recently become clear that B cell receptor (BCR) activation plays an important role in the pathogenesis of chronic lymphocytic leukaemia (CLL); a fact that is underlined by the marked efficacy of drugs that inhibit components of this pathway. Although the underlying mechanisms remain unclear, CLL BCRs have been shown to recognize a variety of autoantigens and there is evidence of ongoing activation of a number of downstream signaling molecules including Syk, Erk, Akt and the NFkB and NFAT family of transcription factors. In addition to BCR activation, it is thought that signals from other cells in the tumour microenvironment such as T cells, the vascular endothelium and other stromal cells may also play a role in promoting the growth of the disease. In the present study we chose to revisit the effects of ciclosporin (CsA), a calcineurin antagonist with effects on antigen receptor signaling, in CLL. When this agent is used to treat the autoimmune complications of CLL, concurrent responses in the underlying disease have been noted in about 20% of patients, although the underlying mechanism has not been thoroughly investigated. Since CsA primarily inhibits T cell activation we hypothesized that its effects in CLL might be due to a reduction in T cell mediated co-stimulation in the lymph nodes. We therefore investigated the effect of CsA on the activation of CLL B and T cells using conventional and multispectral imaging flow cytometry to measure the expression of activation markers and the nuclear translocation of NFAT and NFKB family transcription factors. Cells were collected from eight unselected patients with a confirmed diagnosis of CLL for each study. T and B cells were purified by negative immunomagnetic selection and activated by incubation with phorbol ester and ionomycin (PMA/I) or CD40L transfected fibroblasts in the presence of absence of CsA. The activation of CD4+ T cells and CD19+ CLL cells was assessed by staining for CD69/interferon gamma (IFNΥ) and CD69/CD25 respectively. Nuclear translocation of NFATc2 and NFKB p65 was measured by image flow cytometry (Amnis Imagestream). Leukaemia and Lymphoma Research provided the funding for this study. NFkB(p65) translocation at 30 minutes was inhibited by a mean of 22.5% (p=0.0003) in activated CLL CD4+ T cells treated with CsA compared to those treated with vehicle control (VC). Similarly, in the presence of CsA, NFAT-c2 translocation was inhibited by a mean of 24.3% (p=0.008) at 10 minutes in CLL CD4+ T cells compared to those treated with VC. NFkB(p65) translocation was not inhibited (mean of differences=0.63%, p=0.645) and NFAT-c2 translocation was minimally inhibited (mean of differences = -4%, p = 0.007) in activated CLL B Cells treated with CsA. The proportion of activated CLL CD4+ T cells expressing both CD69 and IFNΥ was reduced by 13.2% (p=0.003) in the presence of CsA whereas there was no inhibition of CD25(-1.5, p=0.16) and CD69(-1.4, p=0.5) expression in activated CLL B cells treated with CsA. In summary, CsA had a profound effect on CD4+ T cell activation in patients with CLL, as demonstrated by the reduction in NFkB (p65), NFAT-c2 nuclear translocation and CD69/IFNΥ expressing cells. In contrast, there was a minimal effect on NFAT-c2 translocation in activated CLL B cells and no impact on NFkB (p65) translocation or the expression of CD25 and CD69. These findings suggest that the previously documented activity of CsA in CLL is not due to a direct effect on the tumour but is instead indirect and mediated through inhibition of other microenvironment derived signals such as those provided by activated CD4+ T cells. Since it is likely that these co-stimulatory effects act in concert other signals, such as those induced by BCR activation, reexamination of CsA and similar agents in CLL would thus seem warranted. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Ligation of Cytotoxic T Lymphocyte Antigen-4 to T Cell Receptor Inhibits T Cell Activation and Directs Differentiation into Foxp3+Regulatory T Cells

2012 ◽  
Vol 287 (14) ◽  
pp. 11098-11107 ◽  
Author(s):  
Jozsef Karman ◽  
Ji-Lei Jiang ◽  
Nathan Gumlaw ◽  
Hongmei Zhao ◽  
Juanita Campos-Rivera ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Lymphocyte Antigen
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