Induction of T cell unresponsiveness by anti‐CD3 antibodies occurs independently of co‐stimulatory functions

Andris, Fabienne; Mechelen, Marcelle Van; Mattia, Fabrizio De; Baus, Erika; Urbain, Jacques; Léo, Oberdan

doi:10.1002/eji.1830260534

Cited by 23 publications

(15 citation statements)

References 48 publications

(23 reference statements)

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“…As previously demonstrated by us and others (17,25), anti-CD3 mAb administration in mice led to T cell unresponsiveness to a subsequent in vitro stimulation by soluble anti-CD3 and accessory cells (Fig. 1A).…”

Section: Anti-cd3 Mabs Do Not Induce Naive T Cell Anergy In Vivosupporting

confidence: 84%

“…As cells were cultured in the absence of exogenous growth factors, a progressive decline in cell viability was observed in control cultures lacking anti-CD3 stimuli. However, culture conditions did not modify the ability of control populations to respond to TCR-mediated stimulations, as cells cultured in the absence of agonists and freshly purified cells responded in similar fashion to receptor triggering (15,25) (data not shown). Therefore, in most experiments, freshly purified CD4 ϩ T cells were used as unstimulated controls.…”

Section: Cell Purifications and In Vitro Treatmentsmentioning

confidence: 94%

“…For stimulations with soluble anti-CD3 mAbs, Fluo-3-loaded T cells (400 l) were incubated with anti-CD3 mAbs (clone 7D6, 0.5 g/ml) for 2 min at 37°C, cross-linked by secondary rabbit anti-mouse Abs, and analyzed for Fluo-3 emission at 525 nm with the CellQuest software (BD Biosciences), as previously described (25).…”

Section: Calcium Mobilization Assaysmentioning

confidence: 99%

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Naive T Cells Are Resistant to Anergy Induction by Anti-CD3 Antibodies

Andris

Denanglaire

Mattia

et al. 2004

The Journal of Immunology

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Anti-CD3 mAbs are potent immunosuppressive agents used in clinical transplantation. It has been generally assumed that one of the anti-CD3 mAb-mediated tolerance mechanisms is through the induction of naive T cell unresponsiveness, often referred to as anergy. We demonstrate in this study that naive T cells stimulated by anti-CD3 mAbs both in vivo and in vitro do not respond to the superantigen staphylococcal enterotoxin B nor to soluble forms of anti-CD3 mAbs and APC, but express increased reactivity to plastic-coated forms of the same anti-CD3 mAbs and to their nominal Ag/class II MHC, a finding that is difficult to rationalize with the concept of anergy. Phenotypic and detailed kinetic studies further suggest that a strong signal 1 delivered by anti-CD3 mAbs in the absence of costimulatory molecules does not lead to anergy, but rather induces naive T cells to change their mitogen responsiveness and acquire features of memory T cells. In marked contrast, Ag-experienced T cells are sensitive to anergy induction under the same experimental settings. Collectively, these studies demonstrate that exposure of naive T cells in vivo and in vitro to a strong TCR stimulus does not induce Ag unresponsiveness, indicating that sensitivity to negative signaling through TCR/CD3 triggering is developmentally regulated in CD4+ T cells.

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Section: Anti-cd3 Mabs Do Not Induce Naive T Cell Anergy In Vivosupporting

confidence: 84%

Section: Cell Purifications and In Vitro Treatmentsmentioning

confidence: 94%

See 1 more Smart Citation

Naive T Cells Are Resistant to Anergy Induction by Anti-CD3 Antibodies

Andris

Denanglaire

Mattia

et al. 2004

The Journal of Immunology

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“…There are a number of reports of CD4 T cells becoming unresponsive following in vitro or in vivo responses to a variety of stimuli including Mls-1 (43), enterotoxin (44), and mitogenic anti-CD3 (45). In experiments examining in vivo and in vitro stimulation with anti-CD3 mAb Andris et al (45) showed that unresponsiveness developed even when the initial response included a contribution from CD28-dependent costimulation.…”

Section: Discussionmentioning

confidence: 99%

Signaling Alterations in Activation-Induced Nonresponsive CD8 T Cells

Tham

Mescher

2001

The Journal of Immunology

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Costimulation-dependent production and autocrine use of IL-2 by activated CD8 T cells results in initial clonal expansion, but this is transient. The cells quickly become anergic, unable to produce IL-2 in response to Ag and costimulation, irrespective of the form of costimulation. This activation-induced non-responsiveness (AINR) differs from “classical” anergy in that it results despite the cells receiving both signal 1 and signal 2. AINR cells can still proliferate in response to exogenous IL-2, but can no longer produce it. Other TCR-mediated events including cytolytic function and IFN-γ production are not affected in the AINR state. To characterize the mechanism(s) responsible for lack of IL-2 production in CD8 T cells in the AINR state, microspheres bearing immobilized anti-TCR Abs or peptide-MHC complexes, B7-1, and ICAM-1 were used to provide well-defined stimuli to the cells. Comparison of normal and AINR cells revealed that in AINR cells extracellular signal-regulated kinase (ERK) is upregulated more transiently, Janus kinase activation is substantially reduced, and activation of p38 is eliminated. PMA and ionomycin restored proliferation and IL-2 production in AINR cells, indicating a signaling defect upstream of Ras and protein kinase C. Inhibitors of ERK (PD98059) and of p38 kinase (SB202190) blocked IL-2 mRNA expression and proliferation of both peptide-MHC/B7-1/ICAM-1-stimulated normal cells and PMA/ionomycin-stimulated AINR cells. Together these results demonstrate that activation of at least ERK and p38 is essential for IL-2 production by CD8 T cells and that up-regulation of these mitogen-activated protein kinases, along with Janus kinase, is defective in AINR cells.

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“…(Manassas, VA, U.S.A.). The I-E k -restricted, pigeon cytochrome-c-specific T-cell hybridoma 3B4 (CD90 + , CD3 + , CD4 + , CD8 − ) was derived by Dr. Fabienne Andris [22]. Murine astrocytes were purified as described in [23].…”

Section: Cell Linesmentioning

confidence: 99%

Distribution of the Src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells

Muraille

Pesesse

Kuntz

et al. 1999

Biochemical Journal

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The termination of activation signals is a critical step in the control of the immune response; perturbation of inhibitory feedback pathways results in profound immune defects culminating in autoimmunity and overwhelming inflammation. FcγRIIB receptor is a well described inhibitory receptor. The ligation of B-cell receptor (BCR) and FcγRIIB leads to the inhibition of B-cell activation. Numerous studies have demonstrated that the SH2-domain-containing inositol 5-phosphatase SHIP (referred hereto as SHIP-1) is essential in this process. The cDNA encoding a second SH2-domain-containing inositol 5-phosphatase, SHIP-2, has been cloned [Pesesse, Deleu, De Smedt, Drayer and Erneux (1997) Biochem. Biophys. Res. Commun. 239, 697-700]. Here we report the distribution of SHIP-2 in mouse tissues: a Western blot analysis of mouse tissues reveals that SHIP-2 is expressed in both haemopoietic and non-haemopoietic cells. In addition to T-cell and B-cell lines, spleen, thymus and lung are shown to coexpress SHIP-1 and SHIP-2. Moreover, SHIP-2 is detected in fibroblasts, heart and different brain areas. SHIP-2 shows a maximal tyrosine phosphorylation and association to Shc after ligation of BCR to FcγRIIB but not after stimulation of BCR alone. Our results therefore suggest a possible role for SHIP-2 in the negative regulation of immunocompetent cells.

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Induction of T cell unresponsiveness by anti‐CD3 antibodies occurs independently of co‐stimulatory functions

Cited by 23 publications

References 48 publications

Naive T Cells Are Resistant to Anergy Induction by Anti-CD3 Antibodies

Naive T Cells Are Resistant to Anergy Induction by Anti-CD3 Antibodies

Signaling Alterations in Activation-Induced Nonresponsive CD8 T Cells

Distribution of the Src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells

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