ARRESTED REARRANGEMENT OF TCR V-BETA GENES IN THYMOCYTES FROM CHILDREN WITH X-LINKED SEVERE COMBINED IMMUNODEFICIENCY DISEASE

Human X-linked severe combined immunodeficiency disease (SCID) is an i mmunodeficiency disorder in which T cell development is arrested in th e thymic cortex. B lymphocytes in children with X-linked SCID seem to differentiate normally. X-linked SCID is associated with a mutation in the gene that encodes the IL-2R gamma-chain. Because TCR-beta gene re combination is a pivotal initial event in T lymphocyte ontogeny within the thymus, we hypothesized that a failure to express normal IL-2R ga mma could lead to impaired TCR-beta gene recombination in early thymic development. PCR was used to determine the status of TCR-beta gene-se gment rearrangements in thymic DNA that had been obtained from childre n with X-linked SCID. The initial step in TCR-beta gene rearrangement, that of D beta to J beta recombination, was readily detected in all t hymus samples from children with X-linked SCID; in contrast, V beta to DJ beta gene rearrangements were undetectable in the same samples. Bo th D beta to J beta and V beta to DJ beta TCR genes were rearranged in the thymic tissues obtained from immunologically normal children. We conclude that TCR beta-chain gene rearrangement is arrested in childre n with X-linked SCID. Our results suggest a causative relationship bet ween the failure of TCR beta-chain gene rearrangements to proceed beyo nd DJ beta rearrangements and the production of a nonfunctional IL-2R gamma-chain.