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.