EpCAM identifies a developmentally poised DN thymocyte subset that drives T-cell production

While stromal degeneration is a known cause, the intrinsic heterogeneity and regulatory mechanisms within early thymocyte progenitors are poorly understood. Here, we report that the epithelial cell adhesion molecule (EpCAM), conventionally a marker of thymic epithelial cells, identifies a functionally distinct subset within double-negative (DN) thymocytes.

EpCAM⁺ DN cells are transcriptionally and epigenetically primed for T-cell lineage commitment, exhibit superior proliferative and differentiation potential in vitro, and serve as the dominant precursors for T-cell reconstitution in vivo. This progenitor pool expands acutely following thymic injury but undergoes pronounced contraction with age, a trajectory conserved in the human thymus. Our findings redefine EpCAM as a marker of a developmentally competent DN thymocyte state, whose erosion contributes to thymic involution and presents a potential target for regenerative strategies.