Jagged2-Expressing Hematopoietic Progenitors Promote Regulatory T Cell Expansion in the Periphery through Notch Signaling

SummaryCellular interactions promoting the in vivo expansion of CD4+CD25+Foxp3+ regulatory T (Treg) cells for maintenance of immune tolerance remain poorly defined. Here we report that mobilized Lin−Sca-1+c-kit+ (LSK) hematopoietic progenitor cells (HPCs), unlike medullary hematopoietic stem cells (HSCs), selectively drove the direct, immediate expansion of functional host-derived Treg cells, thereby preventing the progression to overt spontaneous autoimmune diabetes in nonobese diabetic mice. Treg cell expansion required cell-to-cell contact and Notch3 signaling, which was mediated selectively through the Notch ligand Jagged2 expressed by the multipotent HPC subset, as assessed by small interfering RNA (siRNA) silencing. Conversely, notwithstanding their similar multilineage microchimerism, neither sorted Jagged2− HPCs nor Jagged2lo medullary HSCs were able to expand Treg cells. These data provide evidence for a productive Notch-mediated interaction between a unique subset of mobilized hematopoietic progenitors and Treg cells. They open therapeutic perspectives for autologous transplantation of Jagged2+ LSK progenitors to promote Treg cell expansion in T cell-mediated diseases.