A Dapl1+ subpopulation of naïve CD8 T cells is enriched for memory-lineage precursors

Sci Adv. 2025 Aug 22;11(34):eadx5687. doi: 10.1126/sciadv.adx5687. Epub 2025 Aug 22.

Abstract

Memory CD8 T cells provide long-lasting immunity, but their developmental origins remain incompletely defined. Growing evidence suggests that functional heterogeneity exists within the naïve T cell pool, shaping lineage potential before antigen stimulation. Here, we identify a subpopulation of naïve CD8 T cells expressing death-associated protein-like 1 (Dapl1) that contains preprogrammed precursors biased toward memory differentiation. The differentiation of these precursors is independent of Dapl1 but relies on the transcription factor B-cell lymphoma/leukaemia 11b (Bcl11b), resulting in the generation of Dapl1+ central memory-like CD8 T cells after infection and stem-like memory cells in cancer. Dapl1+ naïve T cells originate among mature thymocytes and gradually appear in the periphery postnatally. Peripheral Dapl1+ and Dapl1- populations show limited plasticity, supporting a thymic-imprinting model. These findings reveal a developmentally imprinted subset of naïve CD8 T cells committed to memory fate, uncovering an alternative pathway for memory T cell generation offering new avenues for therapeutic application.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins* / genetics
  • Apoptosis Regulatory Proteins* / metabolism
  • CD8-Positive T-Lymphocytes* / cytology
  • CD8-Positive T-Lymphocytes* / immunology
  • CD8-Positive T-Lymphocytes* / metabolism
  • Cell Differentiation / immunology
  • Cell Lineage*
  • Immunologic Memory*
  • Memory T Cells* / cytology
  • Memory T Cells* / immunology
  • Memory T Cells* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Bcl11b protein, mouse
  • Repressor Proteins
  • Tumor Suppressor Proteins