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.

Expression of Serum microRNAs is Altered During Acute Graft-versus-Host Disease

“…To verify the NanoString data, 10 microRNAs (miR-146a, miR-30b-5p, miR-374-5p, miR-20a, miR-15a, miR-181a, miR-18a, miR-19a, miR-19b, and miR-451a) were selected for further assessment in the diagnostic verification cohort (Table 2), based on those with high FC and/or reported in the literature to be implicated in GvHD, T-cell function, or the inflammatory response (13, 26–32). …”

miR-181a Expression in Donor T Cells Modulates Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation

“…Because the impact of mitochondrial proteins on clonal expansion of activated T cells has been described (23), the regulation of different targets in functionally different pathways by miR-181a (phosphatases downstream of TCR, regulators of mitochondrial apoptosis, and PTEN among others) may result in a more complex phenotype, although the relative importance of each individual pathway remains to be determined. Interestingly, Wu et al (6) observed BCL-2 and PTEN as a target of the miR-17-92 cluster. Whereas the threshold for TCR signaling may be lowered by miR-181a, its expression has to be limited to maintain the balance of pro-and anti-apoptotic signals in activated T cells.…”

“…Furthermore, increased miR-146a expression in donor T cells prevents from GvHD development by targeting TNFR-associated factor 6, leading to reduced TNF transcription (5). It has also been shown that blocking the miR17-92 cluster alleviates aGvHD while preserving the graftversus-leukemia (GvL) effect (6).…”

miR-153-3p, a new bio-target, is involved in the pathogenesis of acute graft-versus-host disease via inhibition of indoleamine- 2,3-dioxygenase

“…It indicated that miR-153 might be related to some immune-related diseases, including GVHD. The majority of the miRs related to aGVHD have been shown to function in T or B lymphocytes [11, 12, 22]. However, IDO might inhibit aGVHD development through various types of cells in addition to lymphocytes, such as dendritic cells (DCs), mesenchymal stem cells (MSCs) and myeloid-derived suppressor cells (MDSCs).…”