Chronic graft-versus-host disease (cGVHD) is characterized as autoimmune-like fibrosis
and antibody production mediated by pathogenic T cells and B cells. MicroRNA-17-92
(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,
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
T helper 1 (Th1) and Th17 cells, but also promotes the generation of follicular Th
cells, germinal center (GC) B cells, and plasma cells. In B cells, miR-17-92 expression
is required for autoantibody production and immunoglobulin G 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.