Islet-derived CD105+ stromal cells release autoantigens via exosomes secretion: activation of autoreactive T and B cells in NOD mice (P4131)

Abstract

Abstract Exosomes (EXO) are secreted, nano-size membrane vesicles that contain potent immunostimulatory materials. We have recently demonstrated that insulinoma-released EXO carry islet antigens and activate autoreactive T- cells in non-obese diabetic (NOD) mice, a spontaneous disease model for type 1 diabetes (T1D). To investigate whether primary islet cells in NOD can produce EXO, we isolated cells from the islet of Langerhans and cultured them in vitro. Interestingly, cultured islets release fibroblast-like, self-replicating cells that express mesenchymal stem cell makers such as CD105, Sca-1 and CD90 molecules. These islet stromal cells (iSC) release EXO that are highly immunostimulatory to activate lymphocytes and induce inflammatory cytokines and chemokines. The EXO-induced IFN-gamma production is clearly associated with the autoreactivity of the lymphocytes and the progression of T1D in the mice. These results support that iSC may release unique autoantigens via EXO secretion that may trigger islet-specific autoimmunity. Consistent with these observations, immune histological analysis of pancreata showed that CD105+ stromal cells restrict to the peri-islet area in normal islets but penetrate into beta cell area as lymphocyte infiltration occurs. In addition, serum EXO level in NOD mice is dramatically increased at prediabetic stage, possibly following the islet inflammation. Thus, EXO are autoantigen carriers with unique adjuvant activities and may activate autoreactive cells.