title: ATM deficiency disrupts Tcra locus integrity and the maturation of CD4+CD8+ thymocytes.
abstract: Mutations in ATM (ataxia-telangiectasia mutated) cause ataxia-telangiectasia (AT), a disease characterized by neurodegeneration, sterility, immunodeficiency, and T-cell leukemia. Defective ATM-mediated DNA damage responses underlie many aspects of the AT syndrome, but the basis for the immune deficiency has not been defined. ATM associates with DNA double-strand breaks (DSBs), and some evidence suggests that ATM may regulate V(D)J recombination. However, it remains unclear how ATM loss compromises lymphocyte development in vivo. Here, we show that T-cell receptor beta (TCRbeta)-dependent proliferation and production of TCRbeta(low) CD4+CD8+ (DP) thymocytes occurred normally in Atm-/- mice. In striking contrast, the postmitotic maturation of TCRbeta(low) DP precursors into TCRbeta(int) DP cells and TCRbeta(hi) mature thymocytes was profoundly impaired. Furthermore, Atm-/- thymocytes expressed abnormally low amounts of TCRalpha mRNA and protein. These defects were not attributable to the induction of a BCL-2-sensitive apoptotic pathway. Rather, they were associated with frequent biallelic loss of distal Va gene segments in DP thymocytes, revealing that ATM maintains Tcra locus integrity as it undergoes V(D)J recombination. Collectively, our data demonstrate that ATM loss increases the frequency of aberrant Tcra deletion events, which compromise DP thymocyte maturation and likely promote the generation of oncogenic TCR translocations.
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, University of Toronto, ON, Canada.
authors.forename: Irina R
authors.initials: IR
authors.lastname: Matei
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Gladdy
authors.forename: Lauryl M J
authors.initials: LM
authors.lastname: Nutter
authors.forename: Angelo
authors.initials: A
authors.lastname: Canty
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidos
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Danska
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases