Myeloid-derived suppressor cells prevent type 1 diabetes in murine models
Effective immunotherapy of Type 1 diabetes (T1D) relies on active induction of peripheral tolerance. Myeloid-derived suppressor cells (MDSCs) play a critical role in suppressing immune responses in various pathologic settings via multiple mechanisms, including expansion of T regulatory cells (Tregs). Here, we investigated whether MDSCs could act as antigen presenting cells to induce expansion of antigen-specific Tregs and suppress T-cell proliferation, and whether the immunosuppressive properties of MDSCs could be harnessed to prevent autoimmune T1D development. We found that MDSC-mediated expansion of Tregs and T-cell suppression required MHC dependent antigen presentation. Therefore, a murine T1D model with the defined surrogate autoantigen, influenza hemagglutinin (HA), was used in which INS-HA/RAG-/- mice were adoptively transferred with antigen specific T cells isolated from CD4-HA-TCR transgenic mice. We found a significant reduction in the incidence of diabetes in recipients receiving MDSC plus HA, but not OVA peptide, leading to 75% diabetes-free mice in treated animals. The pancreata of these mice showed significantly lower levels of lymphocyte infiltration in the islets and insulitis compared to the control groups. The protective effects of MDSCs might be mediated by inducing anergy in auto-reactive T cells and the development of CD4+CD25+Foxp3+ Tregs. The present study demonstrated a remarkable capacity of transferred MDSCs in down-regulating the antigen-specific autoimmune response and preventing diabetes onset in a murine model, and suggests that MDSCs possess great potential as a novel cell-based tolerogenic therapy in the control of T1D and other autoimmune diseases.