MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice
Blood, The Journal of the American Society of Hematology, 2015•ashpublications.org
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 …
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 …
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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