title: Regulation of TCRβ allelic exclusion by gene segment proximity and accessibility.
abstract: Ag receptor loci are regulated to promote allelic exclusion, but the mechanisms are not well understood. Assembly of a functional TCR β-chain gene triggers feedback inhibition of V(β)-to-DJ(β) recombination in double-positive (DP) thymocytes, which correlates with reduced V(β) chromatin accessibility and a locus conformational change that separates V(β) from DJ(β) gene segments. We previously generated a Tcrb allele that maintained V(β) accessibility but was still subject to feedback inhibition in DP thymocytes. We have now further analyzed the contributions of chromatin accessibility and locus conformation to feedback inhibition using two novel TCR alleles. We show that reduced V(β) accessibility and increased distance between V(β) and DJ(β) gene segments both enforce feedback inhibition in DP thymocytes.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Hrisavgi D
authors.initials: HD
authors.lastname: Kondilis-Mangum
authors.forename: Han-Yu
authors.initials: HY
authors.lastname: Shih
authors.forename: Grace
authors.initials: G
authors.lastname: Mahowald
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sleckman
authors.forename: Michael S
authors.initials: MS
authors.lastname: Krangel
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000276:immunology; D025461:Feedback, Physiological; D005787:Gene Frequency / Q000276:immunology*; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor / Q000235:genetics; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009690:Nucleic Acid Conformation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D011995:Recombination, Genetic / Q000276:immunology*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; C090377:pre-T cell receptor alpha
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