Skewed T-cell receptor repertoire, decreased thymic output, and predominance of terminally differentiated T cells in ataxia telangiectasia

Giovannetti, Antonello; Mazzetta, Francesca; Caprini, Elisabetta; Aiuti, Alessandro; Marziali, Marco; Pierdominici, Marina; Cossarizza, Andrea; Chessa, Luciana; Scala, Enrico; Quinti, Isabella; Russo, Giandomenico; Fiorilli, Massimo

doi:10.1182/blood-2002-03-0976

Cited by 74 publications

(70 citation statements)

References 51 publications

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“…It is known that in some pathological conditions, a defective pool of naive T lymphocytes can be replaced by peripheral expansion of T lymphocytes with severely restricted TCR repertoires [17,[26][27][28][29]. This is not the case in our patients, because we observed only minor clonal expansions in the context of dominant polyclonal T cell populations.…”

Section: Discussioncontrasting

confidence: 40%

Reduced thymic output, increased spontaneous apoptosis and oligoclonal B cells in polyethylene glycol-adenosine deaminase-treated patients

Malacarne

Benicchi

Notarangelo³

et al. 2005

Eur. J. Immunol.

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Impairment of purine metabolism due to adenosine deaminase (ADA) deficiency is associated with a severe combined immunodeficiency (SCID). Polyethylene glycolmodified ADA (PEG-ADA) has provided noncurative, life-saving treatment for these patients, but full immune recovery is not achieved with this therapy. Since ADA-SCID is perhaps the most difficult form of SCID to handle clinically, understanding the benefits and limitations of PEG-ADA therapy may be relevant for treatment selection. To this purpose, we analyzed the rate of thymic output, T and B cell repertoires, number of T cell divisions, IFN-c and IL-4 production, and the extent of cell death in five ADA-SCID patients following a prolonged period of treatment with PEG-ADA. We found that thymic output was low in these patients. However, their T cell repertoire was heterogeneous, and their T lymphocytes produced cytokines upon activation and responded to mitogen stimulation, although with different kinetics. Furthermore, a high number of peripheral T lymphocytes were committed to apoptosis. Anomalies were also observed in the B cell compartment, with oligoclonal expansions of B cell clonotypes in two patients. Our data indicate that decreased thymic function, B cell oligoclonality, and increased spontaneous apoptosis may be the mechanisms by which the immunodeficiency of ADA-SCID patients persists in spite of treatment with PEG-ADA.

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Section: Discussioncontrasting

confidence: 40%

Reduced thymic output, increased spontaneous apoptosis and oligoclonal B cells in polyethylene glycol-adenosine deaminase-treated patients

Malacarne

Benicchi

Notarangelo³

et al. 2005

Eur. J. Immunol.

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“…A significant number of A-T patients have immunodeficiencies that affect skin Ag test responses, responses to alloantigens or mitogens, and production of T cell-dependent IgE, IgA, and IgG4 Abs (2)(3)(4). Defects in thymocyte development and a reduction in peripheral T cells numbers have also been observed in A-T patients (5,6) and Atm-deficient mice (Atm Ϫ/Ϫ mice) (7,8). These defects appear to be related to the role of Atm in T cells rather than the Atm-deficient thymic environment in which these cells develop (9).…”

Section: A Taxia-telangiectasia (A-t)mentioning

confidence: 99%

Regulation of Oxidative Stress Responses by Ataxia-Telangiectasia Mutated Is Required for T Cell Proliferation

Bagley

Singh

Iacomini

2007

The Journal of Immunology

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Mutations in the gene encoding ataxia-telangiectasia (A-T) mutated (Atm) cause the disease A-T, characterized by immunodeficiency, the molecular basis of which is not known. Following stimulation through the TCR, Atm-deficient T cells and normal T cells in which Atm is inhibited undergo apoptosis rather than proliferation. Apoptosis is prevented by scavenging reactive oxygen species (ROS) during activation. Atm therefore plays a critical role in T cell proliferation by regulating responses to ROS generated following T cell activation. The inability of Atm-deficient T cells to control responses to ROS is therefore the molecular basis of immunodeficiency associated with A-T.

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“…Peripheral T cell depletion associated with increased serum IL-7 concentration and consequent CD95 upregulation in lymphopenic individuals has been reported in HIV patients (12) and bone marrow transplant recipients (13). Significantly higher CD95 expression on A-T patient T cells compared with controls has also been described, although IL-7 was not investigated (5,7).…”

mentioning

confidence: 97%

“…They have reduced proportions of naive T and naive B cells and increased proportions of memory T cells, memory B cells, and NK cells compared with normal healthy individuals (5). The cause of the T cell lymphopenia in A-T patients is thought to be reduced output from the thymus (6), although increased spontaneous apoptosis of naive cells was suggested as a contributing factor (7).…”

mentioning

confidence: 99%

Classical Ataxia Telangiectasia Patients Have a Congenitally Aged Immune System with High Expression of CD95

Carney

Srinivasan

Moss

et al. 2012

The Journal of Immunology

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Ataxia-telangiectasia (A-T) is a rare neurodegenerative immunodeficiency disorder caused by mutations in the ataxia telangiectasia mutated gene. Patients commonly have lymphopenia and Ig-production abnormalities. We used multicolor flow cytometry and IL-7 ELISA to investigate the effect of A-T and age on the proportions of major lymphocyte subsets and their pattern of CD95 expression in relation to IL-7 levels in 15 classical A-T patients. We also analyzed the sensitivity of T cells from four classical A-T patients to CD95-mediated apoptosis using TUNEL and caspase-activation assays. Our results confirmed lymphopenia and a deficiency in naive T and B cells in A-T patients. In contrast to controls, the proportions of naive and memory T and B cell subsets in A-T patients did not vary in relation to age. There was no evidence of a deficiency in plasma IL-7 or IL-7R expression, and IL-7 concentration correlated positively with CD95 expression on CD4+ T cells. CD95 expression on unstimulated A-T lymphocytes was high, and the apoptotic sensitivity of activated naive and central memory T cells was increased. These findings show that the immunodeficiency in A-T patients may be described as congenitally aged and is not progressive. The naive cell deficiency is not related to a deficiency in IL-7 or its receptor. However, IL-7 may upregulate CD95 on A-T lymphocytes. High CD95 expression and increased apoptotic sensitivity of activated naive and central memory T cells may result in an increased level of CD95-mediated apoptosis, which could contribute to the congenital lymphopenia in A-T.

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Skewed T-cell receptor repertoire, decreased thymic output, and predominance of terminally differentiated T cells in ataxia telangiectasia

Cited by 74 publications

References 51 publications

Reduced thymic output, increased spontaneous apoptosis and oligoclonal B cells in polyethylene glycol-adenosine deaminase-treated patients

Reduced thymic output, increased spontaneous apoptosis and oligoclonal B cells in polyethylene glycol-adenosine deaminase-treated patients

Regulation of Oxidative Stress Responses by Ataxia-Telangiectasia Mutated Is Required for T Cell Proliferation

Classical Ataxia Telangiectasia Patients Have a Congenitally Aged Immune System with High Expression of CD95

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