Constitutive Impaired TCR/CD3-mediated Activation of T cells in IDDM Patients Co-exist with Normal Co-stimulation Pathways

Nervi, Solange; Atlan-Gepner, C; Fossat, C.; Vialettes, B.

doi:10.1006/jaut.1999.0313

Cited by 19 publications

(8 citation statements)

References 48 publications

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“…This hyporesponsiveness, characterized by a reduced in vitro TCR/CD3-mediated T cell proliferation (6,7,36,42), is correlated with an inefficient activation of PKC and/or p21 ras activation pathways, low expression of the early T cell activation marker CD69, and IL-2 secretion. The defective T cell response can be compensated by the addition of the PKC-activating drug PMA, and is not observed with a combination of agonistic anti-CD2/CD28 mAbs (7).…”

Section: Discussionmentioning

confidence: 99%

“…To investigate the molecular basis for the lymphocyte hyporesponsiveness from type 1 diabetic patients (6,7,23), PBMC were activated with an anti-CD3 mAb, and the global pattern of tyrosine phosphorylation was analyzed in cell lysates. Differences were observed both in resting and activation conditions.…”

Section: Altered Pattern Of Protein Tyrosine Phosphorylation In Pbmcsmentioning

confidence: 99%

“…All these modifications of the TCR/ CD3-dependent activation cascade seem to locate a putative defect during the early stages of NOD thymocyte activation. We have recently characterized a cohort of diabetic patients in whom a similar defect in TCR/CD3-mediated activation was documented (7). In this study, a more systematic analysis of the early activation stages in peripheral T cells was performed.…”

mentioning

confidence: 97%

“…The involvement of other predisposition genes is suspected to explain the numerous immunological abnormalities shared in different models of type 1 diabetes. In humans, one of these immune phenotypes is characterized by low proliferation and poor cytokine production by T lymphocyte in response to TCR/CD3-mediated agonists in vitro (6,7). The reduced T cell activation can be partially compensated by additional costimulatory signals, such as combinations of CD2/CD28 mAbs or exogenous cytokines.…”

mentioning

confidence: 99%

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Specific Deficiency of p56lck Expression in T Lymphocytes from Type 1 Diabetic Patients

Nervi

Atlan-Gepner

Kahn-Perlès

et al. 2000

The Journal of Immunology

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Peripheral T lymphocyte activation in response to TCR/CD3 stimulation is reduced in type 1 diabetic patients. To explore the basis of this deficiency, a comprehensive analysis of the signal transduction pathway downstream of the TCR/CD3 complex was performed for a cohort of patients (n = 38). The main result of the study shows that T cell hyporesponsiveness is positively correlated with a reduced amount of p56lck in resting T lymphocytes. Upon CD3-mediated activation, this defect leads to a hypophosphorylation of the CD3ζ-chain and few other polypeptides without affecting the recruitment of ZAP70. Other downstream effectors of the TCR/CD3 transduction machinery, such as phosphatidylinositol 3-kinase p85α, p59fyn, linker for activation of T cells (LAT), and phospholipase C-γ1, are not affected. In some patients, the severity of this phenotypic deficit could be linked to low levels of p56lck mRNA and resulted in the failure to efficiently induce the expression of the CD69 early activation marker. We propose that a primary deficiency in human type 1 diabetes is a defect in TCR/CD3-mediated T cell activation due to the abnormal expression of the p56lck tyrosine kinase.

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Section: Discussionmentioning

confidence: 99%

Section: Altered Pattern Of Protein Tyrosine Phosphorylation In Pbmcsmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

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Specific Deficiency of p56lck Expression in T Lymphocytes from Type 1 Diabetic Patients

Nervi

Atlan-Gepner

Kahn-Perlès

et al. 2000

The Journal of Immunology

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“…Such hyporesponsive T cells have been reported in T1D patients in vitro [129] and in rodent autoimmune-prone models ex vivo [130]. However, much remains to be determined regarding the significance of the IL2RA genotype-sCD25 correlation; any functionality of sCD25 is unknown, as is the actual cellular origin of it, as there is evidence that non-T cells can also produce it (see the next section).…”

Section: Non-regulatory T Cells and T1dmentioning

confidence: 95%

The IL-2/CD25 Pathway Determines Susceptibility to T1D in Humans and NOD Mice

Dendrou

Wicker

2008

J Clin Immunol

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Ex vivo TCR‐induced leukocyte gene expression of inflammatory mediators is increased in type 1 diabetic patients but not in overweight children

Rosa

Mitsuhashi

Oliver

et al. 2009

Diabetes Metabolism Res

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Abnormal systemic concentrations of proinflammatory cytokines/chemokines have been implicated in the development of long-term cardiovascular complications in type 1 diabetes (T1DM) and obesity. Whether leukocyte (WBC) gene expression of these proinflammatory mediators contributes to their increased systemic levels, however, remains unclear, especially in the pediatric patient populations. This study examines mRNA changes of 9 cytokines and chemokines in WBCs following ex vivo immunostimulation from 9 T1DM (13.4±0.5 yr, 4F/5M), 23 overweight (OW, 12.3±0.5 yr, 10F/13M, BMI% 97.1±0.5 and >90.0), and 21 healthy (CL, 13.8±0.7 yr, 9F/12M, BMI% 59.6±4.6 and <85.0) children. All subjects had been maintained in euglycemic conditions for at least 90 min before blood draws. Whole blood was then sampled and incubated with anti-T-cell receptor (TCR) antibody or heat-aggregated IgG (HAG) to stimulate Tcell and Fc receptors, respectively. After lysis of leukocytes, mRNA levels of 6 TNF superfamily cytokines (TNFSF2,5,6,7,9,14) and 3 chemokines (CCL8, 20, and CXCL10) were measured using RT-PCR. Following TCR stimulation, T1DM displayed significantly greater mRNA responses than CL for TNFSF5, 7, 9, and CCL8, and CXCL10; TNFSF9, CCL8, and CXCL10 were also significantly higher in T1DM than OW; no difference was observed between OW and CL. Fc receptor (FcR) stimulation induced similar responses across groups. Therefore, leukocytes of T1DM children displayed exaggerated gene expression in response to ex vivo TCR induction of 5 key proinflammatory cytokines/chemokines. This elevated leukocyte gene expression may be one of the pathophysiological contributors to the development of vascular complications in T1DM.

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Constitutive Impaired TCR/CD3-mediated Activation of T cells in IDDM Patients Co-exist with Normal Co-stimulation Pathways

Cited by 19 publications

References 48 publications

Specific Deficiency of p56lck Expression in T Lymphocytes from Type 1 Diabetic Patients

Specific Deficiency of p56lck Expression in T Lymphocytes from Type 1 Diabetic Patients

The IL-2/CD25 Pathway Determines Susceptibility to T1D in Humans and NOD Mice

Ex vivo TCR‐induced leukocyte gene expression of inflammatory mediators is increased in type 1 diabetic patients but not in overweight children

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