Abstract
Hematopoietic stem cells (HSCs) with multilineage potential are critical for effective T cell reconstitution and restoration of the adaptive immune system after allogeneic Hematopoietic Cell Transplantation (allo-HCT). The Kit (lo) subset of HSCs is enriched for multipotential precursors, (1, 2) but their T-cell lineage potential has not been well-characterized. We therefore studied the thymic reconstituting and T-cell potential of Kit (lo) HSCs. Using a preclinical allo-HCT model, we demonstrate that Kit (lo) HSCs support better thymic recovery, and T-cell reconstitution resulting in improved T cell responses to infection post-HCT. Furthermore, Kit (lo) HSCs with augmented BM lymphopoiesis mitigate age-associated thymic alterations, thus enhancing T-cell recovery in middle-aged hosts. We find the frequency of the Kit (lo) subset declines with age, providing one explanation for the reduced frequency of T-competent HSCs and reduced T-lymphopoietic potential in BM precursors of aged mice. (3, 4, 5) Chromatin profiling revealed that Kit (lo) HSCs exhibit higher activity of lymphoid-specifying transcription factors (TFs), including Zbtb1 . Deletion of Zbtb1 in Kit (lo) HSCs diminished their T-cell potential, while reinstating Zbtb1 in megakaryocytic-biased Kit (hi) HSCs rescued T-cell potential, in vitro and in vivo . Finally, we discover an analogous Kit (lo) HSC subset with enhanced lymphoid potential in human bone marrow. Our results demonstrate that Kit (lo) HSCs with enhanced lymphoid potential have a distinct underlying epigenetic program.