The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20061460
The Journal of Experimental Medicine, Vol. 204, No. 6, 1371-1381
The Rockefeller University Press, 0022-1007 $30.00
© Huang et al.
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ARTICLE

 Defects in coding joint formation in vivo in developing ATM-deficient B and T lymphocytes

Ching-Yu Huang1, Girdhar G. Sharma2, Laura M. Walker1, Craig H. Bassing3,4, Tej K. Pandita2, and Barry P. Sleckman1

1 Department of Pathology and Immunology and 2 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110
3 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
4 Abramson Family Cancer Research Institute of the University of Pennsylvania Cancer Center, Philadelphia, PA 19104

CORRESPONDENCE Barry P. Sleckman: Sleckman{at}immunology.wustl.edu

Ataxia-telangiectasia mutated (ATM)–deficient lymphocytes exhibit defects in coding joint formation during V(D)J recombination in vitro. Similar defects in vivo should affect both T and B cell development, yet the lymphoid phenotypes of ATM deficiency are more pronounced in the T cell compartment. In this regard, ATM-deficient mice exhibit a preferential T lymphopenia and have an increased incidence of nontransformed and transformed T cells with T cell receptor {alpha}/{delta} locus translocations. We demonstrate that there is an increase in the accumulation of unrepaired coding ends during different steps of antigen receptor gene assembly at both the immunoglobulin and T cell receptor loci in developing ATM-deficient B and T lymphocytes. Furthermore, we show that the frequency of ATM-deficient {alpha}ß T cells with translocations involving the T cell receptor {alpha}/{delta} locus is directly related to the number of T cell receptor {alpha} rearrangements that these cells can make during development. Collectively, these findings demonstrate that ATM deficiency leads to broad defects in coding joint formation in developing B and T lymphocytes in vivo, and they provide a potential molecular explanation as to why the developmental impact of these defects could be more pronounced in the T cell compartment.

Abbreviations used: AMuLV pre–B cell, v-abl–transformed mouse pre–B cell line; A-T, ataxia-telangiectasia; ATM, A-T mutated; BCR, B cell receptor; CE, coding end; DN, double negative; DP, double positive; DSB, double-strand break; JNK, c-Jun N-terminal kinase; LMPCR, ligation-mediated PCR; P8, probe 8; PR2, RAG-2 probe; PS6, SJA probe 6; RS, recombination signal; SE, signal end; WCP, whole chromosome paint.


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