title: Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD.
abstract: During allogeneic hematopoietic cell transplantation (alloHCT), nonhematopoietic cell interleukin-33 (IL-33) is augmented and released by recipient conditioning to promote type 1 alloimmunity and lethal acute graft-versus-host disease (GVHD). Yet, IL-33 is highly pleiotropic and exhibits potent immunoregulatory properties in the absence of coincident proinflammatory stimuli. We tested whether peri-alloHCT IL-33 delivery can protect against development of GVHD by augmenting IL-33-associated regulatory mechanisms. IL-33 administration augmented the frequency of regulatory T cells (Tregs) expressing the IL-33 receptor, suppression of tumorigenicity-2 (ST2), which persist following total body irradiation. ST2 expression is not exclusive to Tregs and IL-33 expands innate immune cells with regulatory or reparative properties. However, selective depletion of recipient Foxp3(+) cells concurrent with peri-alloHCT IL-33 administration accelerated acute GVHD lethality. IL-33-expanded Tregs protected recipients from GVHD by controlling macrophage activation and preventing accumulation of effector T cells in GVHD-target tissue. IL-33 stimulation of ST2 on Tregs activates p38 MAPK, which drives expansion of the ST2(+) Treg subset. Associated mechanistic studies revealed that proliferating Tregs exhibit IL-33-independent upregulation of ST2 and the adoptive transfer of st2(+) but not st2(-) Tregs mediated GVHD protection. In total, these data demonstrate the protective capacity of peri-alloHCT administration of IL-33 and IL-33-responsive Tregs in mouse models of acute GVHD. These findings provide strong support that the immunoregulatory relationship between IL-33 and Tregs can be harnessed therapeutically to prevent GVHD after alloHCT for treatment of malignancy or as a means for tolerance induction in solid organ transplantation.
authors.affiliation: Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA;
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Matta
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Dawn K
authors.identifier: 0000-0002-3855-5541
authors.initials: DK
authors.lastname: Reichenbach
authors.affiliation: Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA; Xiangya School of Medicine, Central South University, Changsha, Hunan, China;
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA;
authors.forename: Lisa
authors.initials: L
authors.lastname: Mathews
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Brent H
authors.initials: BH
authors.lastname: Koehn
authors.affiliation: Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA;
authors.forename: Gaelen K
authors.initials: GK
authors.lastname: Dwyer
authors.affiliation: Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA;
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Lott
authors.affiliation: Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University Medical Center Freiburg, Albert-Ludwigs University, Freiburg, Germany;
authors.forename: Franziska M
authors.initials: FM
authors.lastname: Uhl
authors.affiliation: Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University Medical Center Freiburg, Albert-Ludwigs University, Freiburg, Germany;
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Colby J
authors.initials: CJ
authors.lastname: Feser
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Smith
authors.affiliation: Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China;
authors.forename: Quan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Hematology and Oncology, University Medical Center, Albert-Ludwigs University, Freiburg, Germany; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Bruce R
authors.identifier: 0000-0002-9608-9841
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Hēth R
authors.identifier: 0000-0002-4173-4014
authors.initials: HR
authors.lastname: Turnquist
mesh_terms: D000208:Acute Disease; D064591:Allografts; D000818:Animals; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000235:genetics / Q000276:immunology*; D000067596:Interleukin-33 / Q000276:immunology*; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D036102:Peripheral Blood Stem Cell Transplantation; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory
chemical_list: C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D018123:Receptors, Interleukin