The Mechanism of Chromosome 7 Inversion in Human Lymphocytes Expressing Chimeric γβ TCR

Functional chimeric TCR chains, encoded by VγJγCβ or VγJβCβ hybrid gene TCR, are expressed at the surface of a small fraction of αβ T lymphocytes in healthy individuals. Their frequency is dramatically increased in patients with ataxia-telangiectasia, a syndrome associated with inherited genomic instability. As the TCR γ and β loci are in an inverted orientation on chromosome 7, the generation of such hybrid genes requires at least an inversion event. Until now, neither the sequences involved in this genetic mechanism nor the number of recombinations leading to the formation of functional transcriptional units have been characterized. In this manuscript, we demonstrate that at least two rearrangements, involving classical recombination signal sequence and the V(D)J recombinase complex, lead to the formation of productive hybrid genes. A primary inversion 7 event between Dβ and Jγ genic segments generates CγVβ and CβVγ hybrid loci. Within the CγVβ locus, secondary rearrangements between Vγ and Jγ or Vγ and Jβ elements generate functional genes. Besides, our results suggest that secondary rearrangements were blocked in the CβVγ locus of normal but not ataxia-telangiectasia T lymphocytes. We also provide formal evidence that the same Dβ-3′ recombination signal sequence can be used in successive rearrangements with Jγ and Jβ genic segments, thus showing that a signal joint has been involved in a secondary recombination event.