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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-03-0976. This Article Full Text (PDF) All Versions of this Article: 2002-03-0976v1 100/12/4082    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Giovannetti, A. Articles by Fiorilli, M. Search for Related Content PubMed PubMed Citation Articles by Giovannetti, A. Articles by Fiorilli, M. Social Bookmarking                   What's this? Submitted March 29, 2002 Accepted July 8, 2002 Skewed T cell receptor repertoire, decreased thymic output, and predominance of terminally differentiated T cells in ataxia-telangiectasia Antonello Giovannetti*, Francesca Mazzetta, Elisabetta Caprini, Alessandro Aiuti, Marco Marziali, Marina Pierdominici, Andrea Cossarizza, Luciana Chessa, Enrico Scala, Isabella Quinti, Giandomenico Russo, and Massimo Fiorilli Clinical Immunology and Allergy, University of Rome, Rome, Italy Molecular Oncogenesis Laboratory, IDI - IRCCS, Rome, Italy Telethon Institute for Gene Therapy, San Raffaele Institute, Milan, Italy Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy Department of Experimental Medicine and Pathology, University of Rome, Rome, Italy * Corresponding author; email: antonello.giovannetti{at}uniroma1.it. Ataxia telangiectasia, a genetic disorder caused by the homozygous mutation of the ATM gene, frequently associates with variable degrees of cellular and humoral immunodeficiency. However, the immune defects occurring in AT patients are still poorly characterized. Here we show that the T cell receptor (TCR) variable ß(BV) chain repertoire of nine A-T patients was restricted by diffuse expansions of some variable genes prevalently occurring within the CD4 subset and clustering to certain TCRBV genes (e.g. 5.1, 11, 14 and 23). In addition, the study of the third determining complementarity region (CDR3) showed, in all patients, significantly altered profiles in most BV genes examined suggesting diffuse oligoclonal expansions. The sequencing of TCR CDR3 regions revealed completely normal V(D)J coding joints, and confirmed a reduced diversity of the antigen receptor repertoire. The B cell repertoire was similarly restricted and skewed by diffuse oligoclonal expansions with normal V(D)J joints. Thymic output, evaluated by measuring TCR rearrangement excision circles, was extremely low. The majority of peripheral T cells had the phenotype and the function of effector memory cells, indicating that in vivo they are able to respond normally by terminal differentiation to antigeni stimuliation. These results indicate that ATM mutation limits the generation of a wide repertoire of normally functioning T and B cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Bagley, G. Singh, and J. Iacomini Regulation of Oxidative Stress Responses by Ataxia-Telangiectasia Mutated Is Required for T Cell Proliferation J. Immunol., April 15, 2007; 178(8): 4757 - 4763. [Abstract] [Full Text] [PDF] A. Giovannetti, M. Pierdominici, F. Mazzetta, M. Marziali, C. Renzi, A. M. Mileo, M. De Felice, B. 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