biostudies-literatureUnknown11(34)Lynch ACMemory 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.Science advanceseadx5687https://www.ebi.ac.uk/biostudies/studies/S-EPMC12372879biostudies-literatureA Dapl1⁺ subpopulation of naive CD8 T cells is enriched for memory-lineage precursors.PMC12372879Alfandari DLiang XCui WHioki KAThesmar ICernjul JHe XDMager JPobezinsky LALynch ACPobezinskaya ELfalseA Dapl1⁺ subpopulation of naive CD8 T cells is enriched for memory-lineage precursors.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.2025-01-01T00:00:00Z2025 Aug2026-05-09T10:44:41.127Z2026-04-08T00:48:23.743ZS-EPMC123728794084511210.1126/sciadv.adx5687