GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion.
Allelic exclusion describes the essential immunological process by which feedback repression of sequential DNA rearrangements ensures that only one autosome expresses a functional T or B cell receptor. In wild-type mammals, approximately 60% of cells have recombined the DNA of one T cell receptor β (TCRβ) V-to-DJ-joined allele in a functional configuration, while the second allele has recombined only the DJ sequences; the other 40% of cells have recombined the V to the DJ segments on both alleles, with only one of the two alleles predicting a functional TCRβ protein. Here we report that the transgenic overexpression of GATA3 leads predominantly to biallelic TCRβ gene (Tcrb) recombination. We also found that wild-type immature thymocytes can be separated into distinct populations based on intracellular GATA3 expression and that GATA3LOcells had almost exclusively recombined only oneTcrblocus (that predicted a functional receptor sequence), while GATA3HIcells had uniformly recombined bothTcrballeles (one predicting a functional and the other predicting a nonfunctional rearrangement). These data show that GATA3 abundance regulates the recombination propensity at theTcrblocus and provide new mechanistic insight into the historic immunological conundrum for howTcrballelic exclusion is mediated.
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
Chia-Jui
CJ
Ku
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
JoAnn M
JM
Sekiguchi
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
Bharat
B
Panwar
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
Yuanfang
Y
Guan
Department of Anatomy and Embryology, Faculty of Medicine, International Institute for Integrative Sleep Medicine (WPI-IIIS), Life Science Center, Tsukuba Advanced Research Alliance, and Laboratory Animal Resource Center, University of Tsukuba, Tsukaba, Japan.
Satoru
S
Takahashi
Department of Anatomy and Embryology, Faculty of Medicine, International Institute for Integrative Sleep Medicine (WPI-IIIS), Life Science Center, Tsukuba Advanced Research Alliance, and Laboratory Animal Resource Center, University of Tsukuba, Tsukaba, Japan.
Keigyou
K
Yoh
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.|Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.|Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
Ivan
I
Maillard
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
Tomonori
T
Hosoya
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA engel@umich.edu.
James Douglas
JD
Engel
D000483:Alleles; D000818:Animals; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D063990:Gene Ontology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D017423:Sequence Analysis, RNA; D013154:Spleen / Q000378:metabolism; D060168:Thymocytes / Q000378:metabolism; D060152:V(D)J Recombination / Q000235:genetics
D050990:GATA3 Transcription Factor; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta
GATA3; T cell receptor beta locus; allelic exclusion; monoallelic-to-biallelic switch