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Updated: Jun 3, 2025

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Inactivation of GSK3β by Ser389 phosphorylation prevents thymocyte necroptosis and impacts Tcr repertoire diversity

Felipe Valença-Pereira1, Ryan M Sheridan2, Kent A Riemondy2

  • 1Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA.

Cell Death and Differentiation
|January 8, 2025
PubMed

Insights

T cell development requires DNA repair during gene assembly. This study reveals a survival pathway involving GSK3β inactivation and cell cycle checkpoints, crucial for thymocyte survival and shaping the T cell receptor repertoire.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • T cell receptor (TCR) gene assembly involves DNA double-strand breaks (DSBs) and repair in developing thymocytes.
  • Cell cycle checkpoints and survival mechanisms during TCR gene recombination are not fully understood.

Purpose of the Study:

  • To investigate cell cycle checkpoints and survival pathways in thymocytes during TCR gene (Tcrb and Tcra) V(D)J recombination.
  • To elucidate the role of GSK3β in thymocyte survival and TCR repertoire formation.

Main Methods:

  • High-resolution single-cell RNA sequencing (scRNA-seq) of sorted mouse DN3 and DN4 thymocytes.
  • Analysis of cell cycle status and gene expression during V(D)J recombination.

Main Results:

  • Identified both G1 and G2/M cell cycle checkpoints during Tcrb and Tcra gene recombination.
  • Demonstrated that GSK3β inactivation (phosphorylation at Ser389) is essential for thymocyte survival at these checkpoints.
  • Showed that GSK3β promotes necroptosis, not apoptosis, in thymocytes undergoing V(D)J recombination.
  • Found that failure to inactivate GSK3β alters the Tcrb and Tcra gene repertoire by affecting V segment utilization.

Conclusions:

  • Discovered a novel thymocyte survival pathway critical for DNA repair during V(D)J recombination.
  • GSK3β inactivation is a key regulator of thymocyte survival and T cell receptor repertoire diversity.

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