An epigenetically distinct HSC subset supports thymic reconstitution

Abstract

ABSTRACTHematopoietic 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 Kitlosubset of HSCs is enriched for multipotential precursors,1, 2but their T-cell lineage potential has not been well-characterized. We therefore studied the thymic reconstituting and T-cell potential of KitloHSCs. Using a preclinical allo-HCT model, we demonstrate that KitloHSCs support better thymic recovery, and T-cell reconstitution resulting in improved T cell responses to infection post-HCT. Furthermore, KitloHSCs with augmented BM lymphopoiesis mitigate age-associated thymic alterations, thus enhancing T-cell recovery in middle-aged hosts. We find the frequency of the Kitlosubset 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, 5Chromatin profiling revealed that KitloHSCs exhibit higher activity of lymphoid-specifying transcription factors (TFs), includingZbtb1. Deletion ofZbtb1in KitloHSCs diminished their T-cell potential, while reinstatingZbtb1in megakaryocytic-biased KithiHSCs rescued T-cell potential,in vitroandin vivo. Finally, we discover an analogous KitloHSC subset with enhanced lymphoid potential in human bone marrow. Our results demonstrate that KitloHSCs with enhanced lymphoid potential have a distinct underlying epigenetic program.