Role of GM-CSF in tolerance induction by mobilized hematopoietic progenitors

Mechanisms of protection against autoimmune diseases by transplantation of autologous hematopoietic progenitors remain poorly defined. We recently demonstrated that, unlike medullary hematopoietic stem cells (HSCs), mobilized hematopoietic progenitors (HPCs) stimulate peripheral Foxp3(+) regulatory T cell (Treg)-expansion through cell-contact activation of Notch signaling and through as yet undetermined soluble factor(s), distinct from TGF-beta1. Herein we identified one such soluble factor as granulocyte macrophage-colony stimulating factor (GM-CSF), which is produced at higher levels by HPCs than HSCs and whose neutralization significantly reduces the growth-promoting effect of HPCs on Treg. Treg express a functional GM-CSF receptor alpha-chain CD116 and proliferate in response to this cytokine independently from IL2. GM-CSF-expanded Treg-like HPC-expanded Treg-display enhanced suppressive capacity relative to control Treg. Hence, mobilized progenitors stimulate Treg expansion both by cell-contact dependent mechanisms and by their production of GM-CSF.