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

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.