Fig. 2

Breakdown of self-tolerance mechanism underpins T1D etiology. Briefly, self-tolerance is achieved at two different but related levels. Within the thymus, AIRE promotes the ectopic expression of tissue-specific antigens (TSAs) in thymic epithelial cells (TECs) and together with the presence of thymus resident DC, central tolerance is established through depleting autoreactive T cells (negative selection) and the induction of antigen-specific Treg cells. In parallel, within PLN, DEAF1 drives the ectopic expression of peripheral tissue antigens (PTAs) in lymph node stromal cells (LNSCs)/fibroblastic reticular cells (FRCs) and together with DAP12^hi DCs, peripheral tolerance is established to further solidify immune homeostasis. Abnormalities in organismal tolerizing mechanism is thus fundamental to the pathogenesis of autoimmune disorders including T1D. Tol-DC tolerogenic dendritic cell, Act-DC activated dendritic cell, DAP12 DNAX-activating protein of 12 kDa, DEAF1 deformed epidermal autoregulatory factor 1