| First Author | Hathcock KS | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 4 | Pages | e62188 |
| PubMed ID | 23626787 | Mgi Jnum | J:200634 |
| Mgi Id | MGI:5508975 | Doi | 10.1371/journal.pone.0062188 |
| Citation | Hathcock KS, et al. (2013) ATM influences the efficiency of TCRbeta rearrangement, subsequent TCRbeta-dependent T cell development, and generation of the pre-selection TCRbeta CDR3 repertoire. PLoS One 8(4):e62188 |
| abstractText | Generation and resolution of DNA double-strand breaks is required to assemble antigen-specific receptors from the genes encoding V, D, and J gene segments during recombination. The present report investigates the requirement for ataxia telangiectasia-mutated (ATM) kinase, a component of DNA double-strand break repair, during TCRbeta recombination and in subsequent TCRbeta-dependent repertoire generation and thymocyte development. CD4(-)CD8(-) double negative stage 2/3 thymocytes from ATM-deficient mice have both an increased frequency of cells with DNA break foci at TCRbeta loci and reduced Vbeta-DJbeta rearrangement. Sequencing of TCRbeta complementarity-determining region 3 demonstrates that ATM-deficient CD4(+)CD8(+) double positive thymocytes and peripheral T cells have altered processing of coding ends for both in-frame and out-of-frame TCRbeta rearrangements, providing the unique demonstration that ATM deficiency alters the expressed TCRbeta repertoire by a selection-independent mechanism. ATMKO thymi exhibit a partial developmental block in DN cells as they negotiate the beta-selection checkpoint to become double negative stage 4 and CD4(+)CD8(+) thymocytes, resulting in reduced numbers of CD4(+)CD8(+) cells. Importantly, expression of a rearranged TCRbeta transgene substantially reverses this defect in CD4(+)CD8(+) cells, directly linking a requirement for ATM during endogenous TCRbeta rearrangement to subsequent TCRbeta-dependent stages of development. These results demonstrate that ATM plays an important role in TCRbeta rearrangement, generation of the TCRbeta CDR3 repertoire, and efficient TCRbeta-dependent T cell development. |
