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Blood. 2015 Sep 10;126(11):1314-23. doi: 10.1182/blood-2015-02-627356. Epub 2015 Jul 2.

MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice.

Author information

1
Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, China; Microbiology & Immunology, Medical University of South Carolina, Charleston, SC;
2
Microbiology & Immunology, Medical University of South Carolina, Charleston, SC; Department of Pathology and Cell Biology, University of South Florida, Tampa, FL;
3
Microbiology & Immunology, Medical University of South Carolina, Charleston, SC;
4
Microbiology & Immunology, Medical University of South Carolina, Charleston, SC; Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China;
5
Microbiology & Immunology, Medical University of South Carolina, Charleston, SC; Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China;
6
Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL;
7
Department of Immunology, Duke University Medical Center, Durham, NC; and.
8
Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, China; Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL;
9
Microbiology & Immunology, Medical University of South Carolina, Charleston, SC; Department of Medicine, Medical University of South Carolina, Charleston, SC.

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.

PMID:
26138686
PMCID:
PMC4566810
DOI:
10.1182/blood-2015-02-627356
[Indexed for MEDLINE]
Free PMC Article

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