Cytokine Expanded Myeloid Precursors Function as Regulatory Antigen-Presenting Cells and Promote Tolerance through IL-10-Producing Regulatory T Cells

MacDonald, Kelli P. A.; Rowe, Vanessa; Clouston, Andrew D.; Welply, Joseph K.; Kuns, Rachel D.; Ferrara, James L.M.; Thomas, Ranjeny; Hill, Geoffrey R.

doi:10.4049/jimmunol.174.4.1841

Cited by 128 publications

(136 citation statements)

References 51 publications

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“…49 Further, Waller et al 50 recently found an association between the number of pDCs within BM graft and OS, but failed to show any correlation between pDCs in PBSC and outcome or GVHD.…”

Section: Mobilized Pbsc: the Immunological Perspective F Saraceni Et Almentioning

confidence: 99%

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective

Saraceni

Shem‐Tov

Olivieri

et al. 2015

Bone Marrow Transplant

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Although stem cell mobilization has been performed for more than 20 years, little is known about the effects of mobilizing agents on apheresis composition and the impact of graft cell subsets on patients' outcome. With the increasing use of plerixafor and the inclusion of poor mobilizers in autologous transplant procedures, new parameters other than CD34 + stem cell dose are emerging; plerixafor seems to mobilize more primitive CD34 + /CD38 − stem cells compared with G-CSF, but their correlation with stable hematopoietic engraftment is still obscure. Immune recovery is as crucial as hematopoietic reconstitution, and higher T and natural killer cells infused within the graft have been correlated with better outcome in autologous transplant; recent studies showed increased mobilization of immune effectors with plerixafor compared with G-CSF, but further data are needed to clarify the clinical impact of these findings. In the allogeneic setting, much evidence suggests that mobilized T-cell alloreactivity is tempered by G-CSF, probably with the mediation of dendritic cells, even though no clear correlation with GVL and GVHD has been found. Plerixafor is not approved in healthy donors yet; early data suggest it might mobilize a GVHD protective balance of immune effectors, but further studies are needed to define its role in allogeneic transplant.

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“…49 Further, Waller et al 50 recently found an association between the number of pDCs within BM graft and OS, but failed to show any correlation between pDCs in PBSC and outcome or GVHD.…”

Section: Mobilized Pbsc: the Immunological Perspective F Saraceni Et Almentioning

confidence: 99%

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective

Saraceni

Shem‐Tov

Olivieri

et al. 2015

Bone Marrow Transplant

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“…12,[16][17][18] To study the effect of RelB within recipient APCs, BMCs received 950 cGy (split dose separated by 3 hours on day 0) and were transplanted with 5 ϫ 10 6 bone marrow and 3 ϫ 10 6 purified splenic T cells from Balb/c (allogeneic) or B6 (syngeneic) donors. For donor T reg depletion studies, Balb/c mice were injected intraperitoneally with 500 g anti-CD25 mAb (PC61) or control mAb (rat IgG1 isotype control MAC49) on day Ϫ4 prior to transplantation.…”

Section: Bone Marrow Transplantationmentioning

confidence: 99%

“…19 Animals with severe clinical GVHD (scores Ն 6) were killed according to ethical guidelines, and the day of death was deemed to be the following day, as previously described. 12,16,17,20 Statistics Survival curves were plotted using Kaplan-Meier estimates and compared by log-rank analysis. The Mann Whitney U test was used for the statistical analysis of cytokine data and clinical scores.…”

Section: Assessment Of Gvhdmentioning

confidence: 99%

Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD

MacDonald

Kuns

Rowe

et al. 2007

Blood

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IntroductionAllogeneic bone marrow transplantation (BMT) is the definitive curative therapy for the majority of hematologic malignancies and severe immunodeficiencies. The major complication of allogeneic BMT remains graft-versus-host disease (GVHD) in which the skin, gastrointestinal tract, and liver are preferentially damaged by the transplanted donor immune system. The therapeutic potential of BMT relates to the graft-versus-leukemia (GVL) effect, which eradicates host malignancy after BMT and is mediated by donor T and natural killer cells. 1 GVHD occurs in the majority (50%-70%) of recipients and is largely responsible for the high rate of mortality associated with allogeneic BMT. There is thus a pressing need for new treatment approaches to both prevent and treat GVHD, ideally without inhibiting GVL.The complex interactions resulting in the generation of T-cellmediated alloimmune responses depend on antigen presentation, cognate interactions between donor T cells and antigen-presenting cells (APCs), and the concomitant production of soluble and membrane-bound costimulatory molecules by APCs and T cells (reviewed in Morris et al 2 ). The initiation of GVHD absolutely depends on the presence of mature donor T cells in the graft. 2 Thus, although TLR signaling undoubtedly contributes to the activation of APCs early after transplantation, 3 it is likely that donor T cells provide the most critical signal. In this regard, the CD40-CD40L pathway appears to be of major importance, as demonstrated by the induction of tolerance following disruption of this receptor-ligand interaction. 4 The subsequent molecular mechanisms controlling APC function in tolerance and immunity are poorly defined. The NF-kB/Rel family of proteins include 5 subunits: c-Rel, RelA, RelB, NF-kB1, and NF-kB2, which form homodimers or heterodimers. At steady state, most of these proteins are inactive within the cytoplasm, bound by inhibitory IkB proteins. Activation by the classical pathway within a broad range of cells (including APCs and T cells) occurs as a result of a variety of membrane signals, including TNF, IL-1, and Toll receptors, that allow nuclear import of c-Rel and RelA heterodimers with subsequent transcriptional activation of inflammatory proteins. Activation by the alternative pathway within APCs is the result of lymphocyte interactions and signaling through the lymphotoxin-␤ receptor, BAFF receptor or CD40, resulting in nuclear import of p52/RelB heterodimers and transcriptional activation of characterized and uncharacterized proteins that result in maturation and antigenpresenting activity within professional APCs. [5][6][7] Because APCs are known to be critical for the initiation and maintenance of GVHD 8,9 and their activation occurs rapidly after transplantation, 10 we hypothesized that maintaining host APCs in a state of RelB inactivity during conditioning would promote the induction of peripheral tolerance after allogeneic stem cell transplantation (SCT). We found that the lack of RelB within either host or donor APCs l...

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Kared

Leforban

Montandon

et al. 2008

Blood

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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...

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Cytokine Expanded Myeloid Precursors Function as Regulatory Antigen-Presenting Cells and Promote Tolerance through IL-10-Producing Regulatory T Cells

Cited by 128 publications

References 51 publications

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective

Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD

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

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