CD28 Signal Enhances Apoptosis of CD8 T Cells After Strong TCR Ligation

Yu, Xue-Zhong; Martin, Paul J.; Anasetti, Claudio

doi:10.4049/jimmunol.170.6.3002

Cited by 33 publications

(31 citation statements)

References 39 publications

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“…There have been reports of CD28 having both pro-apoptotic 46,47 and anti-apoptotic effects. [48][49][50] Studies on the aging immune system have found that the number of CD8 þ CD28 À T cells increases with age and that these cells are resistant to apoptosis, having increased bcl-2 expression and decreased caspase 3 expression.…”

Section: Discussionmentioning

confidence: 99%

Distinct gene signature revealed in white blood cells, CD4+ and CD8+ T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide

et al. 2010

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Tolerizing mice polygenically predisposed to lupus-like disease (NZB/NZW F1 females) with a peptide mimicking anti-DNA IgG sequences containing MHC class I and class II T cell determinants (pConsensus, pCons) results in protection from full-blown disease attributable in part to the induction of CD4 þ CD25 þ Foxp3 þ and CD8 þ Foxp3 þ regulatory T cells. We compared 45 000 murine genes in total white blood cells (WBC), CD4 þ T cells, and CD8 þ T cells from splenocytes of (NZBxNZW) F1 lupus-prone mice tolerized with pCons vs untreated naïve mice and found two-fold or greater differential expression for 448 WBC, 174 CD4, and 60 CD8 genes. We identified differentially expressed genes that played roles in the immune response and apoptosis. Using real-time PCR, we validated differential expression of selected genes (IFI202B, Bcl2, Foxp3, Trp-53, CCR7 and IFNar1) in the CD8 þ T cell microarray and determined expression of selected highly upregulated genes in different immune cell subsets. We also determined Smads expression in different immune cell subsets, including CD4 þ T cells and CD8 þ T cells, to detect the effects of TGF-b, known to be the major cytokine that accounts for the suppressive capacity of CD8 þ Treg in this system. Silencing of anti-apoptotic gene Bcl2 or interferon genes (IFI202b and IFNar1 in combination) in CD8 þ T cells from tolerized mice did not affect the expression of the other selected genes. However, silencing of Foxp3 reduced expression of Foxp3, Ifi202b and PD1-all of which are involved in the suppressive capacity of CD8 þ Treg in this model.

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Section: Discussionmentioning

confidence: 99%

Distinct gene signature revealed in white blood cells, CD4+ and CD8+ T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide

et al. 2010

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“…Several studies have demonstrated that costimulation and highavidity ligation of the TCR can play a major role in the negative selection of T cells in the thymus and the periphery (13)(14)(15). By the use of altered peptide ligands (APLs) 3 with different binding affinity to the TCR, it has been shown in CD4 ϩ T cells that differences in TCR activation lead to uncoupling of cytokine production and cell proliferation.…”

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confidence: 99%

Enhanced Levels of Costimulation Lead to Reduced Effector/Memory CD8+ T Cell Functionality

Mostböck

Vidal

Schlom

et al. 2007

The Journal of Immunology

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The role of different levels of costimulation in conjunction with signal 1 in the activation of memory CD8+ T cells remains elusive. In this study, we demonstrate, in a mouse model with the influenza nucleoprotein epitope NP68, that mouse early memory (effector/memory) CD8+ T cells that were generated with high levels of costimulation have reduced CTL functionality compared with those that were generated with low levels of costimulation. This reduction is associated with increased phosphorylation of the negative regulatory site 292 on Zap70 and a decrease in granzyme B levels. Furthermore, we show that enhanced costimulation reduces proliferation and cytokine production of effector/memory CD8+ T cells in response to intermediate and weak TCR stimulation, in contrast to previously described positive effects of costimulation on naive CD8+ T cells. This effect is associated with the expression of ICAM-1 on APCs. Together, our results indicate that enhanced costimulation can lead to reduced functionality in effector/memory CD8+ T cells. This compromised effector function of effector/memory CD8+ T cells in response to high levels of costimulation can have important implications for designing immunotherapeutic strategies to enhance immune responses.

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“…The role of high concentrations of Ag has been investigated using in vitro models and the reports showed a suppression of the proliferative response, which was the consequence of the induction of anergy (3) or apoptosis (4) mediated by CD95/CD178 interaction (5) of CD4 ϩ T cell, whereas in CD8 ϩ effector CTL, apoptosis was mediated by TNFRII/TNF interaction (6,7). In models using TCR transgenic mice, supraoptimal peptide-MHC stimulation in vivo induced CD4 ϩ or CD8 ϩ T cell deletion by apoptosis (4,8,9). In most of these models, deletion of specific T cells occurs after an initial phase of expansion and is thought to result from re-exposure of cycling T lymphocytes to Ag.…”

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confidence: 99%

Cathepsin-Dependent Apoptosis Triggered by Supraoptimal Activation of T Lymphocytes: A Possible Mechanism of High Dose Tolerance

Michallet

Saltel

Flacher

et al. 2004

The Journal of Immunology

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High doses of Ag can paradoxically suppress immune responses in vivo. This Ag-specific unresponsiveness (termed high dose tolerance) involves extrathymic mechanisms in mature T lymphocytes. To investigate these mechanisms, we used the in vitro model of PBL activated with anti-CD3 or PHA. In these conditions, increasing mitogen concentrations resulted in a reduction of the proliferative response, associated with an increased percentage of apoptotic cells. Apoptosis did not require prior exposure to IL-2, it was not the consequence of CD178/CD95 or TNF/TNFR interactions, and was therefore clearly distinct from activation-induced cell death. Although the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) decreased DNA fragmentation, cytochrome c release and caspase-9 and caspase-3 activation were not implicated, suggesting that this apoptosis did not primarily involve the intrinsic mitochondrial pathway. E64d, a cysteine protease inhibitor, as well as specific inhibitors of cathepsin B and cathepsin L conferred protection. We further demonstrated that cathepsin B and cathepsin L were released from the lysosomes and catalytically active in the cytosol. Release of cathepsin B and cathepsin L was the consequence of lysosomal membrane permeabilization without complete disruption of the cytosol-lysosome pH gradient. These results demonstrate a role for cathepsins in supraoptimal activation-induced apoptosis in vitro and suggest their possible participation in high dose tolerance in vivo.

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CD28 Signal Enhances Apoptosis of CD8 T Cells After Strong TCR Ligation

Cited by 33 publications

References 39 publications

Distinct gene signature revealed in white blood cells, CD4+ and CD8+ T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide

Distinct gene signature revealed in white blood cells, CD4+ and CD8+ T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide

Enhanced Levels of Costimulation Lead to Reduced Effector/Memory CD8+ T Cell Functionality

Cathepsin-Dependent Apoptosis Triggered by Supraoptimal Activation of T Lymphocytes: A Possible Mechanism of High Dose Tolerance

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