Schlimgen Ryan J, Reddy Karen L, Singh Harinder, Krangel Michael S
Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nat Immunol. 2008 Jul;9(7):802-9. doi: 10.1038/ni.1624. Epub 2008 Jun 8.
Studies of antigen-receptor loci have linked directed monoallelic association with pericentromeric heterochromatin to the initiation or maintenance of allelic exclusion. Here we provide evidence for a fundamentally different basis for T cell antigen receptor-beta (Tcrb) allelic exclusion. Using three-dimensional immunofluorescence in situ hybridization, we found that germline Tcrb alleles associated stochastically and at high frequency with the nuclear lamina or with pericentromeric heterochromatin in developing thymocytes and that such interactions inhibited variable-to-diversity-joining (V(beta)-to-D(beta)J(beta)) recombination before beta-selection. The introduction of an ectopic enhancer into Tcrb resulted in fewer such interactions and impaired allelic exclusion. We propose that initial V(beta)-to-D(beta)J(beta) recombination events are generally monoallelic in developing thymocytes because of frequent stochastic, rather than directed, interactions of Tcrb alleles with repressive nuclear compartments. Such interactions may be essential for Tcrb allelic exclusion.
对抗原受体基因座的研究已将着丝粒周围异染色质的定向单等位基因关联与等位基因排斥的启动或维持联系起来。在此，我们为T细胞抗原受体β（Tcrb）等位基因排斥提供了一个根本不同的基础证据。利用三维免疫荧光原位杂交技术，我们发现种系Tcrb等位基因在发育中的胸腺细胞中随机且高频地与核纤层或着丝粒周围异染色质相关联，并且这种相互作用在β选择之前抑制了可变区到多样区连接（Vβ到DβJβ）重组。将一个异位增强子引入Tcrb会导致此类相互作用减少，并损害等位基因排斥。我们提出，在发育中的胸腺细胞中，最初的Vβ到DβJβ重组事件通常是单等位基因的，这是因为Tcrb等位基因与抑制性核区室频繁发生随机而非定向的相互作用。此类相互作用可能对Tcrb等位基因排斥至关重要。
