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

• DOI: 10.1016/j.celrep.2021.108967
• Publication Date: 2021-04-15T14:21:49Z
• Authors: Rafael A. Paiva; António G.G. Sousa; Camila V. Ramos; Mariana Ávila; Jingtao Lilue; Tiago Paixão; Vera C. Martins
• Keywords: 0301 basic medicine; EGF Family of Proteins; QH301-705.5; Mice, Transgenic; Thymus Gland; thymus autonomy; Kidney; Lymphocyte Activation; Immunophenotyping; Mice; 03 medical and health sciences; thymus; Animals; Humans; cell competition; Biology (General); Cell Proliferation; T lymphocyte development; Leukemia; Thymocytes; Receptors, Notch; Gene Expression Profiling; Cell Differentiation; T cell acute lymphoblastic leukemia; Hematopoiesis; Mice, Inbred C57BL; Gene Expression Regulation; Single-Cell Analysis; T-ALL; Signal Transduction

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.