The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/12/2233/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 12, December 21, 1998 2233-2241

Articles

Interleukin 7 Receptor Control of T Cell Receptor {gamma} Gene Rearrangement: Role of Receptor-associated Chains and Locus Accessibility

Scott K. Durum*, Serge Candèias{ddagger}, Hiroshi Nakajima§, Warren J. Leonard§, Allison M. Baird||, Leslie J. Berg||, and Kathrin Muegge{ddagger}

From the * Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, Maryland 21702; the {ddagger} Intramural Research Support Program, Science Applications International Corp. Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201; the § Laboratory of Molecular Immunology, National Heart Lung and Blood Institute, Bethesda, Maryland 20892; and the || Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01605

VDJ recombination of T cell receptor and immunoglobulin loci occurs in immature lymphoid cells. Although the molecular mechanisms of DNA cleavage and ligation have become more clear, it is not understood what controls which target loci undergo rearrangement. In interleukin 7 receptor (IL-7R){alpha}–/– murine thymocytes, it has been shown that rearrangement of the T cell receptor (TCR)-{gamma} locus is virtually abrogated, whereas other rearranging loci are less severely affected. By examining different strains of mice with targeted mutations, we now observe that the signaling pathway leading from IL-7R{alpha} to rearrangement of the TCR-{gamma} locus requires the {gamma}c receptor chain and the {gamma}c-associated Janus kinase Jak3. Production of sterile transcripts from the TCR-{gamma} locus, a process that generally precedes rearrangement of a locus, was greatly repressed in IL-7R{alpha}–/– thymocytes. The repressed transcription was not due to a lack in transcription factors since the three transcription factors known to regulate this locus were readily detected in IL-7R{alpha}–/– thymocytes. Instead, the TCR-{gamma} locus was shown to be methylated in IL-7R{alpha}–/– thymocytes. Treatment of IL-7R{alpha}–/– precursor T cells with the specific histone deacetylase inhibitor trichostatin A released the block of TCR-{gamma} gene rearrangement. This data supports the model that IL-7R promotes TCR-{gamma} gene rearrangement by regulating accessibility of the locus via demethylation and histone acetylation of the locus.

Key Words: T cell receptor • thymus • VDJ recombination • interleukin 7 • T cell receptor {gamma} locus • {gamma}/{delta} T cells

Address correspondence to Kathrin Muegge, SAIC, FCRDC, National Cancer Institute, Bldg. 560, Rm. 31-45, Frederick, MD 21702-1201. Phone: 301-846-1386; Fax: 301-846-7077; E-mail: muegge{at}mail.ncifcrf.gov

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

A.M. Baird is a Leukemia Society Fellow for L.J. Berg, and L.J. Berg is supported by grants from the NIH and the American Cancer Society. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-C0-56000.

S. Candèias' present address is CEA-Grenoble, DBMS/ICH, INSERM U238, 17 rue des Martyrs, 38054 Grenoble cedex 9, France.

Abbreviations used: NF, nuclear factor; TSA, trichostatin A; TSLP, thymic stromal-derived lymphopoietin.


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