Interleukin 7 receptor control of T cell receptor gamma gene rearrangement: role of receptor-associated chains and locus accessibility.
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-7Ralpha to rearrangement of the TCR-gamma locus requires the gammac receptor chain and the gammac-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-7Ralpha-/- 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-7Ralpha-/- thymocytes. Instead, the TCR-gamma locus was shown to be methylated in IL-7Ralpha-/- thymocytes. Treatment of IL-7Ralpha-/- 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.
Durum
S K
SK
Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, Maryland 21702, USA.
Candèias
S
S
Nakajima
H
H
Leonard
W J
WJ
Baird
A M
AM
Berg
L J
LJ
Muegge
K
K
D000818:Animals; D001854:Bone Marrow Cells; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor / Q000187:drug effects / Q000235:genetics*; D016654:Genes, RAG-1 / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D053616:Janus Kinase 3; D051379:Mice; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics* / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects / Q000196:embryology; D014157:Transcription Factors / Q000378:metabolism
D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016692:Receptors, Antigen, T-Cell, gamma-delta; D020395:Receptors, Interleukin-7; D014157:Transcription Factors; C012589:trichostatin A; D012313:RNA; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D006655:Histone Deacetylases