Self-renewal of double-negative 3 early thymocytes enables thymus autonomy but compromises the β-selection checkpoint

Cell Rep. 2021 Apr 13;35(2):108967. doi: 10.1016/j.celrep.2021.108967.

Abstract

T lymphocyte differentiation in the steady state is characterized by high cellular turnover whereby thymocytes do not self-renew. However, if deprived of competent progenitors, the thymus can temporarily maintain thymopoiesis autonomously. This bears a heavy cost, because prolongation of thymus autonomy causes leukemia. Here, we show that, at an early stage, thymus autonomy relies on double-negative 3 early (DN3e) thymocytes that acquire stem-cell-like properties. Following competent progenitor deprivation, DN3e thymocytes become long lived, are required for thymus autonomy, differentiate in vivo, and include DNA-label-retaining cells. At the single-cell level, the transcriptional programs of thymopoiesis in autonomy and the steady state are similar. However, a new cell population emerges in autonomy that expresses an aberrant Notch target gene signature and bypasses the β-selection checkpoint. In summary, DN3e thymocytes have the potential to self-renew and differentiate in vivo if cell competition is impaired, but this generates atypical cells, probably the precursors of leukemia.

Keywords: T cell acute lymphoblastic leukemia; T cells; T lymphocyte development; T lymphocytes; T-ALL; cell competition; thymopoiesis; thymus; thymus autonomy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • EGF Family of Proteins / genetics
  • EGF Family of Proteins / immunology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Hematopoiesis / genetics*
  • Hematopoiesis / immunology
  • Humans
  • Immunophenotyping
  • Kidney
  • Leukemia / genetics*
  • Leukemia / immunology
  • Leukemia / pathology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Notch / genetics*
  • Receptors, Notch / immunology
  • Signal Transduction
  • Single-Cell Analysis
  • Thymocytes / classification
  • Thymocytes / immunology*
  • Thymocytes / pathology
  • Thymus Gland / immunology*
  • Thymus Gland / pathology
  • Thymus Gland / transplantation
  • Transcription Factors / genetics*
  • Transcription Factors / immunology
  • Transplantation, Heterotopic
  • Transplantation, Homologous

Substances

  • EGF Family of Proteins
  • Receptors, Notch
  • Transcription Factors