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Brief Definitive Report

The Interleukin 7 Receptor Is Required for T Cell Receptor Locus Accessibility to the V(D)j Recombinase

^a Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3200
^b Laboratory of Molecular Immunoregulation, Science Applications International Corporation (SAIC) Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, Maryland 21702-1201
^c Intramural Research Support Program, Science Applications International Corporation (SAIC) Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, Maryland 21702-1201
SAIC-Frederick Cancer Research and Development Center, National Cancer Institute, Bldg. 560, Rm. 31-45, Frederick, MD 21702-1201.301-846-7077301-846-1386

muegge{at}mail.ncifcrf.gov

Defects in the interleukin (IL)-7 signal transduction pathway lead to severe immunodeficiency in humans and in mice. In IL-7 receptor–deficient (IL-7R^–/–) mice, lymphoid precursors show a reduced survival rate and variable/diversity/joining region V(D)J recombination is variously affected in different loci, being arrested in the T cell receptor (TCR)- locus, aberrant in the immunoglobulin heavy chain (IgH) locus, and delayed in the TCR-β 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-β 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 -β recombination intermediates are readily detectable in normal T1 cells, but only TCR-β 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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