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Mol Cell Biol. 2017 May 31;37(12). pii: e00052-17. doi: 10.1128/MCB.00052-17. Print 2017 Jun 15.

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion.

Author information

1
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
2
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
3
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
4
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.
5
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
6
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
7
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA engel@umich.edu.

Abstract

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 GATA3LO cells had almost exclusively recombined only one Tcrb locus (that predicted a functional receptor sequence), while GATA3HI cells had uniformly recombined both Tcrb alleles (one predicting a functional and the other predicting a nonfunctional rearrangement). These data show that GATA3 abundance regulates the recombination propensity at the Tcrb locus and provide new mechanistic insight into the historic immunological conundrum for how Tcrb allelic exclusion is mediated.

KEYWORDS:

GATA3; T cell receptor beta locus; allelic exclusion; monoallelic-to-biallelic switch

PMID:
28320875
PMCID:
PMC5452726
DOI:
10.1128/MCB.00052-17
[Indexed for MEDLINE]
Free PMC Article

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