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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-03-0976.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4082-4089
IMMUNOBIOLOGY
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
From the Departments of Clinical Medicine and
Experimental Medicine and Pathology, University "La Sapienza," and
Molecular Oncogenesis Laboratory, Istituto Dermopatico dell'
Immacolata, Rome, Italy; San Raffaele Telethon Institute
for Gene Therapy, Milan, Italy; and Department of
Biomedical Sciences, University of Modena and Reggio Emilia,
Italy.
Ataxia telangiectasia (A-T), 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 patients
with A-T are still poorly characterized. Here we show that the T-cell
receptor (TCR) variable  (BV)-chain repertoire of 9 A-T patients
was restricted by diffuse expansions of some variable genes prevalently
occurring within the CD4 subset and clustering to certain TCRBV genes
(eg, 5.1, 11, 14, and 23). In addition, the study of the third
complementarity-determining 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 antigenic stimulation. These
results indicate that ATM mutation limits the generation of
a wide repertoire of normally functioning T and B cells.
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