Defects in coding joint formation in vivo in developing ATM-deficient B and T lymphocytes.
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 alphabeta 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.
Huang
Ching-Yu
CY
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Sharma
Girdhar G
GG
Walker
Laura M
LM
Bassing
Craig H
CH
Pandita
Tej K
TK
Sleckman
Barry P
BP
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000378:metabolism*; D015139:Blotting, Southern; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000172:deficiency*; D005434:Flow Cytometry; D007133:Immunoglobulin Joining Region / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016133:Polymerase Chain Reaction / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000235:genetics; D011995:Recombination, Genetic / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007133:Immunoglobulin Joining Region; D011948:Receptors, Antigen, T-Cell; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases