ATM deficiency impairs thymocyte maturation because of defective resolution of T cell receptor α locus coding end breaks

摘要

The ATM (ataxia telangiectasia mutated) protein plays a central role in sensing and responding to DNA double-strand breaks. Lymphoid cells are unique in undergoing physiologic double-strand breaks in the processes of Ig class switch recombination and T or B cell receptor V(D)J recombination, and a role for ATM in these processes has been suggested by clinical observations in ataxia telangiectasia patients as well as in engineered mice with mutations in the Atm gene. We demonstrate here a defect in thymocyte maturation in ATM-deficient mice that is associated with decreased efficiency in V-J rearrangement of the endogenous T cell receptor (TCR)α locus, accompanied by increased frequency of unresolved TCR Jα coding end breaks. We also demonstrate that a functionally rearranged TCRαβ transgene is sufficient to restore thymocyte maturation, whereas increased thymocyte survival by bcl-2 cannot improve TCRα recombination and T cell development. These data indicate a direct role for ATM in TCR gene recombination in vivo that is critical for surface TCR expression in CD4+CD8+ cells and for efficient thymocyte selection. We propose a unified model for the two major clinical characteristics of ATM deficiency, defective T cell maturation and increased genomic instability, frequently affecting the TCRα locus. In the absence of ATM, delayed TCRα coding joint formation results both in a reduction of αβ TCR-expressing immature cells, leading to inefficient thymocyte selection, and in accumulation of unstable open chromosomal DNA breaks, predisposing to TCRα locus-associated chromosomal abnormalities.