scholarly journals Clonal anergy blocks in vivo growth of mature T cells and can be reversed in the absence of antigen.

1993 ◽  
Vol 177 (5) ◽  
pp. 1517-1521 ◽  
Author(s):  
B Rocha ◽  
C Tanchot ◽  
H Von Boehmer
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Immunological Tolerance ◽  
Receptor Ligands ◽  
In Vivo Growth ◽  
Reactive Lymphocytes ◽  
Clonal Anergy

Experiments in various models have indicated that immunological tolerance can result from the physical elimination (deletion) of reactive lymphocytes as well as from anergy. We have previously reported that mature CD4-CD8+ T cells when confronted with their antigen can proliferate extensively but are finally eliminated or become intrinsically anergic such that remaining cells are refractory to stimulation by any T cell receptor ligands, even in the presence of exogenous interleukin 2. Here we show that in vivo the anergy can be reversed in the absence of antigen, such that the cells are then able to proliferate extensively in vivo to a new challenge with the antigen in question.

Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3065-3072 ◽  
Author(s):  
Michael R. Verneris ◽  
Mobin Karami ◽  
Jeanette Baker ◽  
Anishka Jayaswal ◽  
Robert S. Negrin
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Malignant Cell ◽  
Leukemic Cells ◽  
Target Cells ◽  
High Dose ◽  
Effector Cells ◽  
Nkg2d Expression

Abstract Activating and expanding T cells using T-cell receptor (TCR) cross-linking antibodies and interleukin 2 (IL-2) results in potent cytotoxic effector cells capable of recognizing a broad range of malignant cell targets, including autologous leukemic cells. The mechanism of target cell recognition has previously been unknown. Recent studies show that ligation of NKG2D on natural killer (NK) cells directly induces cytotoxicity, whereas on T cells it costimulates TCR signaling. Here we demonstrate that NKG2D expression is up-regulated upon activation and expansion of human CD8+ T cells. Antibody blocking, redirected cytolysis, and small interfering RNA (siRNA) studies using purified CD8+ T cells demonstrate that cytotoxicity against malignant target cells occurs through NKG2D-mediated recognition and signaling and not through the TCR. Activated and expanded CD8+ T cells develop cytotoxicity after 10 to 14 days of culture, coincident with the expression of the adapter protein DAP10. T cells activated and expanded in low (30 U/mL) and high (300 U/mL) concentrations of IL-2 both up-regulated NKG2D expression equally, but only cells cultured in high-dose IL-2 expressed DAP10 and were cytotoxic. Collectively these results establish that NKG2D triggering accounts for the majority of major histocompatibility complex (MHC)–unrestricted cytotoxicity of activated and expanded CD8+ T cells, likely through DAP10-mediated signaling. (Blood. 2004;103: 3065-3072)

scholarly journals CD27 Expression Promotes Long-Term Survival of Functional Effector–Memory CD8+Cytotoxic T Lymphocytes in HIV-infected Patients

2004 ◽  
Vol 200 (11) ◽  
pp. 1407-1417 ◽  
Author(s):  
Adrian F. Ochsenbein ◽  
Stanley R. Riddell ◽  
Michele Brown ◽  
Lawrence Corey ◽  
Gabriela M. Baerlocher ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Receptor ◽  
Effector Memory ◽  
Term Survival ◽  
Functional Consequences

Human immunodeficiency virus (HIV)-specific CD8+ T cells persist in high frequencies in HIV-infected patients despite impaired CD4+ T helper response to the virus, but, unlike other differentiated effector cytotoxic T lymphocytes, most continue to express the tumor necrosis factor receptor family member CD27. Because the ligand for CD27 (CD70) is also overexpressed in HIV-infected hosts, we examined the nature of expression and potential functional consequences of CD27 expression on HIV-specific CD8+ T cells. Analysis of CD27+ and CD27− T cells derived from the same HIV-specific clone revealed that retention of CD27 did not interfere with acquisition of effector functions, and that after T cell receptor stimulation, CD27+ cells that concurrently were triggered via CD27 exhibited more resistance to apoptosis, interleukin 2 production, and proliferation than CD27− T cells. After transfer back into an HIV-infected patient, autologous HIV-specific CD27− T cells rapidly disappeared, but CD27+ T cells derived from the same clone persisted at high frequency. Our findings suggest that the CD27–CD70 interaction in HIV infection may provide CD27+ CD8+ T cells with a survival advantage and compensate for limiting or absent CD4+ T help to maintain the CD8 response.

Anatomic location and T-cell stimulatory functions of mouse dendritic cell subsets defined by CD4 and CD8 expression

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 2084-2093 ◽  
Author(s):  
Alexander D. McLellan ◽  
Michaela Kapp ◽  
Andreas Eggert ◽  
Christian Linden ◽  
Ursula Bommhardt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Antigen Expression ◽  
Cell Receptor ◽  
In Vitro Assays ◽  
Peptide Complexes ◽  
Marginal Zones

Abstract Mouse spleen contains CD4+, CD8α+, and CD4−/CD8α− dendritic cells (DCs) in a 2:1:1 ratio. An analysis of 70 surface and cytoplasmic antigens revealed several differences in antigen expression between the 3 subsets. Notably, the Birbeck granule–associated Langerin antigen, as well as CD103 (the mouse homologue of the rat DC marker OX62), were specifically expressed by the CD8α+ DC subset. All DC types were apparent in the T-cell areas as well as in the splenic marginal zones and showed similar migratory capacity in collagen lattices. The 3 DC subtypes stimulated allogeneic CD4+ T cells comparably. However, CD8α+ DCs were very weak stimulators of resting or activated allogeneic CD8+ T cells, even at high stimulator-to-responder ratios, although this defect could be overcome under optimal DC/T cell ratios and peptide concentrations using CD8+ F5 T-cell receptor (TCR)–transgenic T cells. CD8α− or CD8α+DCs presented alloantigens with the same efficiency for lysis by cytotoxic T lymphocytes (CTLs), and their turnover rate of class I–peptide complexes was similar, thus neither an inability to present, nor rapid loss of antigenic complexes from CD8α DCs was responsible for the low allostimulatory capacity of CD8α+ DCs in vitro. Surprisingly, both CD8α+ DCs and CD4−/CD8− DCs efficiently primed minor histocompatibility (H-Y male antigen) cytotoxicity following intravenous injection, whereas CD4+ DCs were weak inducers of CTLs. Thus, the inability of CD8α+ DCs to stimulate CD8+ T cells is limited to certain in vitro assays that must lack certain enhancing signals present during in vivo interaction between CD8α+ DCs and CD8+ T cells.

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.

scholarly journals Partial signaling by CD8+ T cells in response to antagonist ligands.

1996 ◽  
Vol 184 (1) ◽  
pp. 149-157 ◽  
Author(s):  
C Reis e Sousa ◽  
E H Levine ◽  
R N Germain
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Phosphorylation ◽  
Cd8 T Cells ◽  
Inositol Phosphates ◽  
Partial Agonist ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Cd4 Cells ◽  
Partial Agonists

Structural variants of an agonist peptide-major histocompatibility complex (MHC) molecule ligand can show partial agonist and/or antagonist properties. A number of such altered ligands appear to act as pure antagonists. They lack any detectable ability to induce T cell effector function and have been described as unable to induce calcium transients and turnover of inositol phosphates. This has been interpreted as an inability of these ligands to initiate any T cell receptor (TCR)-dependent signal transduction, with their antagonist properties ascribed to competition with offered agonist for TCR occupancy. Yet antagonists for mature CD8+ T cells can induce positive selection of thymocytes, implying active induction of T cell differentiation events, and partial agonists or agonist/antagonist combinations elicit a distinctive pattern of early TCR-associated tyrosine phosphorylation events in CD4+ T cells. We have therefore directly examined proximal TCR signaling in a CD8+ T cell line in response to various related ligands. TCR engagement with natural peptide-MHC class I agonist resulted in the same pattern of early TCR-associated tyrosine phosphorylation events as seen with CD4+ cells, including accumulation of both the p21 and p23 forms of phosphorylated zeta, phosphorylation of CD3 epsilon, and association of phosphorylated ZAP-70 with the TCR. Two antagonists that lacked the ability to induce any detectable CTL effector response (cytolysis, esterase release, gamma interferon secretion, interleukin-2 receptor alpha upregulation) were nevertheless found to also induce TCR-dependent phosphorylation events. In these cases, there was preferential accumulation of the p21 form of phospho-zeta without net phosphorylation of CD3 epsilon, as well as the association of nonphosphorylated ZAP-70 kinase with the receptor. These data show that variant ligands induce similar TCR-dependent phosphorylation events in CD8+ T cells as first observed in CD4+ cells. More importantly, they demonstrate that some putatively pure antagonists are actually a subset of partial agonists able to induce intracellular biochemical changes through the TCR. This delivery of a partial signal by antagonists raises the possibility that antagonism in some cases may result from active interference with stimulation of effector activity by agonist in mature T cells, while the same variant signal could selectively trigger intracellular events that allow positive without negative selection in thymocytes.

scholarly journals IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells

2013 ◽  
Vol 210 (3) ◽  
pp. 491-502 ◽  
Author(s):  
Shlomo Z. Ben-Sasson ◽  
Alison Hogg ◽  
Jane Hu-Li ◽  
Paul Wingfield ◽  
Xi Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Interleukin 1 ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
In Vivo Models ◽  
Ifn Γ

Here, we show that interleukin-1 (IL-1) enhances antigen-driven CD8 T cell responses. When administered to recipients of OT-I T cell receptor transgenic CD8 T cells specific for an ovalbumin (OVA) peptide, IL-1 results in an increase in the numbers of wild-type but not IL1R1−/− OT-I cells, particularly in spleen, liver, and lung, upon immunization with OVA and lipopolysaccharide. IL-1 administration also results in an enhancement in the frequency of antigen-specific cells that are granzyme B+, have cytotoxic activity, and/ or produce interferon γ (IFN-γ). Cells primed in the presence of IL-1 display enhanced expression of granzyme B and increased capacity to produce IFN-γ when rechallenged 2 mo after priming. In three in vivo models, IL-1 enhances the protective value of weak immunogens. Thus, IL-1 has a marked enhancing effect on antigen-specific CD8 T cell expansion, differentiation, migration to the periphery, and memory.

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 T cell-mediated eradication of murine metastatic melanoma induced by targeted interleukin 2 therapy.

1996 ◽  
Vol 183 (5) ◽  
pp. 2361-2366 ◽  
Author(s):  
J C Becker ◽  
J D Pancook ◽  
S D Gillies ◽  
K Furukawa ◽  
R A Reisfeld
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Tumor Model ◽  
Melanoma Metastases ◽  
Tumor Eradication

Induction of a T-cell mediated antitumor response is the ultimate goal for tumor immunotherapy. We demonstrate here that antibody-targeted IL2 therapy is effective against established pulmonary and hepatic melanoma metastases in a syngeneic murine tumor model. The effector mechanisms involved in this tumor eradication are not dependent on NK cells, since the therapeutic effect of antibody-IL2 fusion protein was not altered in NK cell-deficient mice. In contrast, T cells are essential for the observed antitumor effect, since therapy with antibody IL2 fusion proteins is unable to induce tumor eradication in T cell-deficient SCID mice. In vivo depletion studies characterized the essential effector cell population further as CD8 + T cells. Such CD8 + T cells, isolated from tumor bearing mice after antibody-directed IL2 therapy, exerted a MHC class I-restricted cytotoxicity against the same tumor in vitro. These data demonstrate the ability of antibody-targeted IL2 delivery to induce a T cell-dependent host immune response that is capable of eradicating established melanoma metastases in clinically relevant organs.

scholarly journals Self-Reactive T Cell Receptor-Reactive CD8+ T Cells Inhibit T Cell Lymphoma Growth In Vivo

2004 ◽  
Vol 173 (11) ◽  
pp. 7062-7069 ◽  
Author(s):  
Marie Gonthier ◽  
Régine Llobera ◽  
Jacques Arnaud ◽  
Bent Rubin
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
Cell Receptor ◽  
T Cell Lymphoma

scholarly journals THE ROLE OF SUBPOPULATIONS OF CD8+ T LYMPHOCYTES IN THE DEVELOPMENT OF PREGNANCY

2018 ◽  
Vol 20 (5) ◽  
pp. 621-638
Author(s):  
O. I. Stepanova ◽  
D. O. Bazhenov ◽  
E. V. Khokhlova ◽  
I. Yu. Kogan ◽  
D. I. Sokolov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Chemokine Receptors ◽  
Cd8 T Cell ◽  
Immunological Tolerance ◽  
Cytolytic Activity ◽  
T Lymphocyte Subsets ◽  
Functional Features

At the present time, a broad spectrum of CD8+ T lymphocyte subsets is revealed, including naïve cells, memory cells and regulatory subpopulations. Along with cells with high cytolytic activity, some subsets with marked regulatory activity were found there. Each subpopulation is characterized by a set of produced mediators, surface and intracellular markers allowing to suggest their differential in vivo functional activity. The present review article proposes a classification of CD8+ Т cells which takes into account their morphological and functional features. According to conventional view, the CD8+ Т lymphocytes is a cell population exhibiting high cytotoxic ability which is of critical significance in pregnancy, under the conditions of semi-allogenic fetal cell invasion into the endometrium. The fraction of CD8+ T cells is rather high in decidual structures. The review discusses the known mechanisms of differentiation regulation, selective migration and activity of CD8+ T cells in decidual membrane and placenta in the course of pregnancy. Perforine and granzyme are the main cytotoxicity factors of CD8+ Т cells. IL-2, IL-5, IL-13, IFNγ, IL-17, TGF-β and IL-10 cytokines are considered regulatory mediators of CD8+ cells. To induce the effector properties of CD8+ T cells, an antigenic stimulation is required, which is provided by interactions between the CD8+ Т cells and activated CD4+ Т cells or dendritic cells, cytokine effects. Specific differentiation of the CD8+ T cells is determined by differences in microenvironvent. In the course of pregnancy, accumulation of CD8+ Т cells is observed in decidual membrane, but their phenotype and functional properties differ from CD8+ Т cells in peripheral blood. At present time, the mechanisms of selective CD8+ T cell migration to decidual membrane are studied. These events are suggested to be mediated by means of CXCR3 and CCR5 chemokine receptors, IL-6 and IL-15 cytokines. The features of CD8+ Т cell activities, and production of some cytokines, e.g., CSF2, IFNγ, IL-1β, IL-2, IL-6, IL-8,IL-10, IL-12 and TNFα in decidual membrane and is of critical significance for effective invasion of trophoblast cells. In turn, the trophoblast and placental cells promote development of regulatory CD8+ Т lymphocytes in decidual membrane, being able to induce CD8+ T cell apoptosis in decidual membrane. Hence, interaction between the maternal CD8+ T cells and trophoblast in the area of uterine-placental contact is an important link during development of immunological tolerance in the maternal/fetal system.

Sign in / Sign up

Export Citation Format

Share Document