title: TCR beta feedback signals inhibit the coupling of recombinationally accessible V beta 14 segments with DJ beta complexes.
abstract: Ag receptor allelic exclusion is thought to occur through monoallelic initiation and subsequent feedback inhibition of recombinational accessibility. However, our previous analysis of mice containing a V(D)J recombination reporter inserted into Vbeta14 (Vbeta14(Rep)) indicated that Vbeta14 chromatin accessibility is biallelic. To determine whether Vbeta14 recombinational accessibility is subject to feedback inhibition, we analyzed TCRbeta rearrangements in Vbeta14(Rep) mice containing a preassembled in-frame transgenic Vbeta8.2Dbeta1Jbeta1.1 or an endogenous Vbeta14Dbeta1Jbeta1.4 rearrangement on the homologous chromosome. Expression of either preassembled VbetaDJbetaC beta-chain accelerated thymocyte development because of enhanced cellular selection, demonstrating that the rate-limiting step in early alphabeta T cell development is the assembly of an in-frame VbetaDJbeta rearrangement. Expression of these preassembled VbetaDJbeta rearrangements inhibited endogenous Vbeta14-to-DJbeta rearrangements as expected. However, in contrast to results predicted by the accepted model of TCRbeta feedback inhibition, we found that expression of these preassembled TCR beta-chains did not downregulate recombinational accessibility of Vbeta14 chromatin. Our findings suggest that TCRbeta-mediated feedback inhibition of Vbeta14 rearrangements depends on inherent properties of Vbeta14, Dbeta, and Jbeta recombination signal sequences.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Yang-Iott
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Carpenter
authors.forename: Marta A W
authors.initials: MA
authors.lastname: Rowh
authors.forename: Natalie
authors.initials: N
authors.lastname: Steinel
authors.forename: Brenna L
authors.initials: BL
authors.lastname: Brady
authors.forename: Konrad
authors.initials: K
authors.lastname: Hochedlinger
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.forename: Craig H
authors.initials: CH
authors.lastname: Bassing
mesh_terms: D000818:Animals; D000916:Antibody Diversity / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002843:Chromatin / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000276:immunology; D015329:Gene Rearrangement, T-Lymphocyte / Q000276:immunology*; D017930:Genes, Reporter / Q000276:immunology; D018095:Germ-Line Mutation / Q000276:immunology; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D019656:Loss of Heterozygosity / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D002843:Chromatin; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D016693:Receptors, Antigen, T-Cell, alpha-beta