title: MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice.
abstract: MicroRNAs (miRs) play important roles in orchestrating many aspects of the immune response. The miR-17-92 cluster, which encodes 6 miRs including 17, 18a, 19a, 20a, 19b-1, and 92-1, is among the best characterized of these miRs. The miR-17-92 cluster has been shown to regulate a variety of immune responses including infection, tumor, and autoimmunity, but the role of this cluster in T-cell response to alloantigens has not been previously explored. By using major histocompatibility complex (MHC)-matched, -mismatched, and haploidentical murine models of allogeneic bone marrow transplantation (allo-BMT), we demonstrate that the expression of miR-17-92 on donor T cells is essential for the induction of graft-versus-host disease (GVHD), but dispensable for the graft-versus-leukemia (GVL) effect. The miR-17-92 plays a major role in promoting CD4 T-cell activation, proliferation, survival, and Th1 differentiation, while inhibiting Th2 and iTreg differentiation. Alternatively, miR-17-92 may promote migration of CD8 T cells to GVHD target organs, but has minimal impact on CD8 T-cell proliferation, survival, or cytolytic function, which could contribute to the preserved GVL effect mediated by T cells deficient for miR-17-92. Furthermore, we evaluated a translational approach and found that systemic administration of antagomir to block miR-17 or miR-19b in this cluster significantly inhibited alloreactive T-cell expansion and interferon-γ (IFNγ) production, and prolonged the survival in recipients afflicted with GVHD while preserving the GVL effect. Taken together, the current work provides a strong rationale and demonstrates the feasibility to target miR-17-92 for the control of GVHD while preserving GVL activity after allo-BMT.
authors.affiliation: Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, China; Microbiology & Immunology, Medical University of South Carolina, Charleston, SC;
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Microbiology & Immunology, Medical University of South Carolina, Charleston, SC; Department of Pathology and Cell Biology, University of South Florida, Tampa, FL;
authors.forename: Jessica
authors.initials: J
authors.lastname: Heinrichs
authors.affiliation: Microbiology & Immunology, Medical University of South Carolina, Charleston, SC;
authors.forename: David
authors.initials: D
authors.lastname: Bastian
authors.affiliation: Microbiology & Immunology, Medical University of South Carolina, Charleston, SC;
authors.forename: Jianing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Microbiology & Immunology, Medical University of South Carolina, Charleston, SC;
authors.forename: Hung
authors.initials: H
authors.lastname: Nguyen
authors.affiliation: Microbiology & Immunology, Medical University of South Carolina, Charleston, SC;
authors.forename: Steven
authors.initials: S
authors.lastname: Schutt
authors.affiliation: Microbiology & Immunology, Medical University of South Carolina, Charleston, SC; Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China;
authors.forename: Yuejun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Microbiology & Immunology, Medical University of South Carolina, Charleston, SC; Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China;
authors.forename: Junfei
authors.initials: J
authors.lastname: Jin
authors.affiliation: Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL;
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC; and.
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
authors.affiliation: Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, China; Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL;
authors.forename: Changqing
authors.initials: C
authors.lastname: Xia
authors.affiliation: Microbiology & Immunology, Medical University of South Carolina, Charleston, SC; Department of Medicine, Medical University of South Carolina, Charleston, SC.
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
mesh_terms: D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology*; D020544:Graft vs Leukemia Effect / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007942:Leukemia, Experimental / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology*; D009841:Oligonucleotides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; C477371:locked nucleic acid; D007371:Interferon-gamma