Disruption of the lineage restriction of TCR beta gene rearrangements.
Despite a common lymphoid recombinase, assembly of Ig genes is restricted to B cells, whereas TCR loci rearrange in T cells. Transcriptional promoters and enhancers are critical for the regulation of the recombination process. However, the specific function of such elements in conferring the lineage-restriction of V(D)J recombination remains poorly understood. To gain further insights into the mechanism restricting TCR beta-chain rearrangements to T cells, we generated mice in which an 11 kb region--containing the beta-chain constant region 2 and the TCR beta enhancer (E beta)--was replaced with the B cell specific Ig heavy-chain enhancer (E mu). Unlike the simple E mu to E beta replacement, this mutation allowed significant levels of D beta to J beta as well as V beta to DJ beta rearrangements in both T and B cells. Although the lineage restriction was disrupted, TCR beta allelic exclusion was still efficient in mutated T cells. Together these results demonstrate that changes in the activity of regulatory elements located at the TCR beta constant regions are sufficient to redirect the recombination pattern of TCR beta variable gene segments.
Eyquem
Stéphanie
S
Unité INSERM U462, Paris, France.
Lagresle
Chantal
C
Fasseu
Magali
M
Sigaux
François
F
Bories
Jean-Christophe
JC
D000107:Acetylation; D000483:Alleles; D000818:Animals; D019070:Cell Lineage; D002874:Chromosome Mapping; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D019674:Genes, T-Cell Receptor beta; D006657:Histones / Q000378:metabolism; D007127:Immunoglobulin Constant Regions / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007133:Immunoglobulin Joining Region / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D016133:Polymerase Chain Reaction; D014158:Transcription, Genetic
D006657:Histones; D007127:Immunoglobulin Constant Regions; D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region