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Brief Definitive Report |
Locus Accessibility to the V(D)J Recombinase
Correspondence to: Kathrin Muegge, SAIC-Frederick Cancer Research and Development Center, National Cancer Institute, Bldg. 560, Rm. 31-45, Frederick, MD 21702-1201. Tel:301-846-1386 Fax:301-846-7077 E-mail:muegge{at}mail.ncifcrf.gov.
Released online: 20 March 2000
locus, aberrant in the immunoglobulin heavy chain (IgH) locus, and delayed in the TCR-ß locus. Here, we analyze the recombination defect of the TCR- locus. Using ligation-mediated polymerase chain reaction, we sought intermediates of the recombination process. In the absence of the IL-7 signal, no initiation of recombination of the TCR- locus was observed, whereas recombination intermediates at the TCR-ß locus could be detected. Thus, the failure to rearrange the TCR- locus is due to a failure to initiate cleavage rather than a failure to religate broken DNA ends. V(D)J recombination was previously thought to begin at the pro-T2 stage of T cell development after the arrest of IL-7R-/- thymocytes at the pro-T1 stage. However, here we show that both TCR- and -ß recombination intermediates are readily detectable in normal T1 cells, but only TCR-ß intermediates were detected in IL-7R-/- T1 cells, supporting a mechanistic role for IL-7 in TCR- locus rearrangement. Since reduced recombination activating gene (rag) expression has been reported in the absence of the IL-7 signal, we directly tested whether the TCR- locus is accessible to cleavage by recombinant Rag proteins in vitro. We found a reduction in chromatin accessibility for Rag-mediated cleavage in IL-7R-/- thymocytes compared with wild-type. Thus, IL-7 controls recombination at the TCR- locus by regulating locus accessibility.
Key Words: recombination, T lymphocytes, interleukins, chromatin, immunology
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