Expression of terminal deoxynucleotidyl transferase (TdT) identifies lymphoid-primed progenitors in human bone marrow

With emerging single-cell techniques in the human hematopoiesis, discrepancies between the traditional cell-surface-marker-based cell-type identification and their single-cell level molecular phenotype are observed. To better associate lymphoid identity with protein-level cell features, we examined the protein expression of terminal deoxynucleotidyl transferase (TdT), a specialized DNA polymerase intrinsic to VDJ recombination, and detected TdT expression within CD34+ progenitors prior to B/T cell emergence. While these TdT+ cells coincided with granulocyte-monocyte progenitor (GMP) immunophenotype, their accessible chromatin regions showed enrichment for lymphoid-associated transcription factor (TF) motifs. TdT expression on GMPs was inversely related to the SLAM family member CD84. Prospective isolation of CD84lo GMPs demonstrated robust lymphoid potential ex vivo, while still retaining significant myeloid differentiation capacity, akin to LMPPs. This multi-omic study identifies previously unappreciated lymphoid-primed progenitors, redefining the lympho-myeloid axis in human hematopoiesis.