Effects of Aire on perforin expression in BMDCs via TLR7/8 and its therapeutic effect on type 1 diabetes

Aims: Type 1 diabetes, as a kind of autoimmune diseases, usually results from the broken-down of self-tolerance. Autoimmune regulator (Aire), as a transcription factor, induces peripheral tolerance by regulating Toll-like Receptor (TLR) expression in dendritic cells (DCs). Several studies have recently identified a small population of perforin-expressing DCs, which is an important population of tolerogenic DCs (tolDCs) that restricts autoreactive T cells in vivo through a perforin-mediated mechanism. Thus, the present study explored the specific relationship among Aire, perforin-expressing DCs and immune tolerance, as well as their roles in type 1 diabetes.

Methods: We conducted studies based on the Aire-overexpressing bone marrow-derived dendritic cell (BMDC) model. And through in vitro and in vivo experiments to observe that Aire-overexpressing BMDCs which express perforin induce immune tolerance and treat type 1 diabetes via TLR7/8.

Results: Aire enhances the expression of perforin in BMDCs after treatment with the TLR7/8 ligand as well as promotes the expression of TLR7/8 and myeloid differentiation primary response gene 88 (MyD88)-dependent pathway molecules. Aire-overexpressing BMDCs mediate Apoptosis of allogeneic CD8⁺ T cells via perforin in vitro. Moreover, Aire-overexpressing BMDCs enhance the therapeutic effect of type 1 diabetes in non-obese diabetic (NOD) mice via perforin and induce Apoptosis of autoreactive CD8⁺ T cells in vivo.

Conclusions: These results provide an experimental basis for comprehensively elucidating the role and significance of Aire expression in peripheral DCs, thereby providing new ideas for the treatment of autoimmune diseases by using Aire as a target to induce the production of perforin-expressing DCs.

Aire; Apoptosis; Autoimmune diseases; Autoreactive CD8(+) T; BMDC; Perforin; TLR7/8; Type 1 diabetes.