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MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft-versus-host disease in mice

Yongxia Wu, Steven Schutt, Katelyn Paz, Mengmeng Zhang, Ryan P. Flynn, David Bastian, M. Hanief Sofi, Hung Nguyen, Min Dai, Chen Liu, Ying-Jun Chang, Bruce R. Blazar and Xue-Zhong Yu

Key points

  • MiR-17-92 mediates the progression of scleroderma and bronchiolitis obliterans in cGVHD by enhancing T and B-cell responses.

  • Pharmacologically blocking the activity of miR-17-92 with an anti-miR-17 antagomir effectively alleviates cGVHD.

Abstract

Chronic graft-versus-host disease (cGVHD) is characterized as autoimmune-like fibrosis and antibody production mediated by pathogenic T-cells and B-cells. MicroRNA (miR)-17-92 influences the survival, differentiation and function of lymphocytes in cancer, infections and autoimmunity. To determine whether miR-17-92 regulates T- and B-cell responses in cGVHD, we generated mice conditionally deficient for miR-17-92 in T-cells, B-cells, or both. Using murine models of allogeneic bone marrow transplantation (allo-BMT), we demonstrate that expression of miR-17-92 in donor T- and B-cells is essential for the induction of both scleroderma and bronchiolitis obliterans in cGVHD. Mechanistically, miR-17-92 expressed in T-cells not only enhances the differentiation of pathogenic Th1 and Th17 cells, but also promotes the generation of follicular T-helper cells, germinal center (GC) B-cells and plasma cells. In B-cells, miR-17-92 expression is required for autoantibody production and IgG deposition in the skin. Furthermore, we evaluated a translational approach using antagomirs specific for either miR-17 or miR-19, key members in miR-17-92 cluster. In a lupus-like cGVHD model, systemic administration of anti-miR-17, but not anti-miR-19, alleviates clinical manifestations and proteinuria incidence in recipients through inhibiting donor lymphocyte expansion, B-cell activation and GC responses. Blockade of miR-17 also ameliorates skin damage by reducing Th17 differentiation in a scleroderma-cGVHD model. Taken together, our work reveals that miR-17-92 is required for T-cell and B-cell differentiation and function, and thus for the development of cGVHD. Furthermore, pharmacological inhibition of miR-17 represents a potential therapeutic strategy for the prevention of cGVHD.

  • Submitted June 7, 2017.
  • Accepted February 26, 2018.