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

Yongxia Wu, Jessica Heinrichs, David Bastian, Jianing Fu, Hung Nguyen, Steven Schutt, Yuejun Liu, Junfei Jin, Chen Liu, Qi Jing Li, Changqing Xia, Xue Zhong Yu

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1314-1323
Number of pages10
JournalBlood
Volume126
Issue number11
DOIs
StatePublished - Sep 10 2015

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T-cells
Graft vs Host Disease
MicroRNAs
Grafts
Leukemia
T-Lymphocytes
Recurrence
Transplants
Homologous Transplantation
Bone Marrow Transplantation
Cell Proliferation
Bone
Isoantigens
Major Histocompatibility Complex
Autoimmunity
Cell proliferation
Interferons
Cell Survival
Tumors
Chemical activation

All Science Journal Classification (ASJC) codes

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Wu, Y., Heinrichs, J., Bastian, D., Fu, J., Nguyen, H., Schutt, S., ... Yu, X. Z. (2015). MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice. Blood, 126(11), 1314-1323. https://doi.org/10.1182/blood-2015-02-627356
Wu, Yongxia ; Heinrichs, Jessica ; Bastian, David ; Fu, Jianing ; Nguyen, Hung ; Schutt, Steven ; Liu, Yuejun ; Jin, Junfei ; Liu, Chen ; Li, Qi Jing ; Xia, Changqing ; Yu, Xue Zhong. / MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice. In: Blood. 2015 ; Vol. 126, No. 11. pp. 1314-1323.
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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.",
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Wu, Y, Heinrichs, J, Bastian, D, Fu, J, Nguyen, H, Schutt, S, Liu, Y, Jin, J, Liu, C, Li, QJ, Xia, C & Yu, XZ 2015, 'MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice', Blood, vol. 126, no. 11, pp. 1314-1323. https://doi.org/10.1182/blood-2015-02-627356

MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice. / Wu, Yongxia; Heinrichs, Jessica; Bastian, David; Fu, Jianing; Nguyen, Hung; Schutt, Steven; Liu, Yuejun; Jin, Junfei; Liu, Chen; Li, Qi Jing; Xia, Changqing; Yu, Xue Zhong.

In: Blood, Vol. 126, No. 11, 10.09.2015, p. 1314-1323.

Research output: Contribution to journalArticle

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AU - Wu, Yongxia

AU - Heinrichs, Jessica

AU - Bastian, David

AU - Fu, Jianing

AU - Nguyen, Hung

AU - Schutt, Steven

AU - Liu, Yuejun

AU - Jin, Junfei

AU - Liu, Chen

AU - Li, Qi Jing

AU - Xia, Changqing

AU - Yu, Xue Zhong

PY - 2015/9/10

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N2 - 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.

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