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

Abstract

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-␤1. 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 growthpromoting effect of HPCs on Treg. IntroductionMobilized peripheral blood stem cells are increasingly used as an alternative to bone marrow (BM) cells for allogeneic transplantation in cancer patients and, more recently, for autologous transplantation in patients with severe autoimmune diseases. Although in the allogeneic setting regulatory T cell (Treg) accumulation triggered by myeloid Gr1 ϩ CD11b ϩ suppressor cells (MSC) reduces acute graft-versus-host disease (GVHD) 1 but instead worsens chronic GVHD, 2 in autoimmune diseases the expansion of Treg is expected to be beneficial. In the experimental model of spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice, we have recently demonstrated 3 that Lin Ϫ Sca1 hi ckit hi Flt3 ϩ CD34 ϩ CD106 ϩ CD127 Ϫ multipotent hematopoietic progenitor cells (HPCs) mobilized to the spleen by a combination of granulocytecolony stimulating factor (G-CSF) and FMS-like tyrosine kinase 3 ligand (Flt3L), have a tolerogenic potential and that their transplantation halts autoimmune diabetes. In contrast, nonmobilized Lin Ϫ Sca1 hi ckit hi Flt3 Ϫ CD34 Ϫ CD106 lo CD127 Ϫ medullary hematopoietic stem cells (HSCs) have no such effect. This difference was linked to the capacity of HPCs, but not HSCs, to drive the expansion of host-derived CD4 ϩ CD25 ϩ Foxp3 ϩ Treg. Furthermore, restoration of Treg numbers to normal values took place after transplantation with hematopoietic progenitors in patients with juvenile rheumatoid arthritis. 4 In view of all these data, the elucidation of the mechanisms underlying Treg expansion by hematopoietic progenitors became essential. We have demonstrated that a cell-to-cell interaction between HPCs and Treg triggers the stimulation of Notch signaling in Treg and their subsequent proliferation. However, separating HPCs from Treg 3 in transwell experiments only partially blocked Treg expansion by HPCs, suggesting that soluble factor(s) were implicated as well.We now report the identification of one such soluble factor as granulocyte macrophage-colony stimulating factor (GM-CSF), which is produced at higher levels by HPCs than HSCs, and promotes expansion of functional Treg through its specific ␣-chain receptor CD116. Methods MiceWild-type and Rag2 Ϫ/Ϫ -NOD mice were bred in our animal facility under specific pathogen-free conditions. Live animal experiments were approved by the Ministère de l'Agricul...

CCL22-Producing CD8α− Myeloid Dendritic Cells Mediate Regulatory T Cell Recruitment in Response to G-CSF Treatment

“…However, it is very likely that other cells may contribute to the effect of pegG-CSF on Tregs. In this regard, we have previously reported that multipotent hematopoietic progenitors mobilized by G-CSF also promote the expansion of Tregs (22,23). Additionally, we observed that DCs from pegG-CSF-treated mice produced more inflammatory cytokines and chemokines in response to LPS or R848 stimulation than DCs from excipient-treated mice, suggesting that their tolerogenic potential may eventually get lost in infectious or inflammatory conditions (Supplemental Fig.…”

Dendritic Cells Induce Regulatory T Cell Proliferation through Antigen-Dependent and -Independent Interactions

“…Although GM-CSF is known to act on DCs, it has also been shown to augment TCR-induced Treg proliferation through direct effects on Tregs (27). To distinguish whether GM-CSF acted on DCs and/or T cells in enhancing Treg proliferation, we used IL-3b/bc DKO mice, which are unable to signal through the GM-CSFR.…”

“…Several reports investigating the mechanisms regulating the expansion and maintenance of Tregs have focused on the ability of the cytokine GM-CSF to expand this population of T cells (26)(27)(28)(29).…”

Innate pro–B-cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells

“…The first subset to be recognized comprised myeloid progenitors that acquired suppressive properties in tumoral and inflammatory environments (1) and played either detrimental or beneficial roles in different pathological situations. We have reported previously that mobilization with hematopoietic growth factors conferred tolerogenic properties to multipotent hematopoietic progenitors at the multipotent progenitor (MPP2) stage of differentiation that enabled them to promote the expansion of regulatory T cells (2,3), thereby preventing spontaneous autoimmune type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse model. Moreover, parasitic infections were shown to stimulate via IL-25 the emergence of Th2 cytokine-secreting MPPs (MPP Th2 ) that ultimately differentiated into mature cell types with pro-Th2 functions, thus contributing to parasitic clearance (4).…”