A Dapl1+ subpopulation of naive CD8 T cells contains committed precursors of memory lineage.

Memory CD8 T cells play a vital role in providing lasting immune protection, yet their origins remain incompletely understood. Contrary to classical models, emerging evidence suggests that heterogeneity within the naive T cell pool may influence fate decisions prior to antigen encounter. However, the markers of naive T cell heterogeneity have not yet been clearly defined. Here, we describe intraclonal heterogeneity within the naive T cell population marked by the protein Dapl1. Using novel monoclonal antibodies and a reporter-knockout mouse model, we found that Dapl1-positive naive CD8 T cells exhibit distinct phenotypes compared to their Dapl1-negative counterparts. Furthermore, this population includes a subset of pre-programmed precursors biased toward memory lineage fate. The differentiation of these precursors is independent of Dapl1 but relies on the transcription factor Bcl11b, resulting in the generation of Dapl1-positive central memory-like CD8 T cells in response to infection, and stem-like memory cells in response to cancer. Notably, naive Dapl1-positive T cells originate among mature thymocytes and gradually appear in the periphery within several days after birth. Our findings suggest that committed memory precursors in the Dapl1-positive population may represent an alternative pathway for memory CD8 T cell generation, offering new avenues for therapeutic application. ONE-SENTENCE SUMMARYNaive Dapl1 positive CD8 T cells include a pre-programmed subset biased toward differentiation into memory-like T cells.