Defects in coding joint formation in vivo in developing ATM-deficient B and T lymphocytes.
Defects in coding joint formation in vivo in developing ATM-deficient B and T lymphocytes.
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在发展ATM缺乏的B和T淋巴细胞中，体内编码关节形成的缺陷。
DOI：
10.1084/jem.20061460
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发表时间：
2007-06-11
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在体外V(D)J重组过程中，共济失调毛细血管扩张突变（ATM）缺陷淋巴细胞在编码关节形成方面表现出缺陷。体内类似的缺陷会影响T细胞和B细胞的发育，但ATM缺陷的淋巴样表型在T细胞室中更为明显。在这方面，atm缺陷小鼠表现出优先性T淋巴细胞减少，并且具有T细胞受体α/δ位点易位的非转化和转化T细胞的发生率增加。我们证明，在发生atm缺陷的B淋巴细胞和T淋巴细胞中，在抗原受体基因组装的不同步骤中，免疫球蛋白和T细胞受体位点的未修复编码末端的积累都有所增加。此外，我们发现，涉及T细胞受体α/δ位点易位的atm缺陷αβ T细胞的频率与这些细胞在发育过程中可以进行的T细胞受体α重排的数量直接相关。总的来说，这些发现表明，ATM缺乏导致体内发育中的B淋巴细胞和T淋巴细胞在编码关节形成方面存在广泛缺陷，并且它们提供了一种潜在的分子解释，为什么这些缺陷的发育影响在T细胞区室中更为明显。
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 α/δ 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 αβ T cells with translocations involving the T cell receptor α/δ locus is directly related to the number of T cell receptor α 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.