STING/type I interferon pathway is required for antigen-containing PLGA nanoparticle- and apoptotic cell-induced CD4+ T cell tolerance.

Autoreactive CD4+ T cell infiltration, tissue destruction, and spread epitope-specific CD4+ T cell activation underly CD4+ T cell-mediated autoimmune disease pathogenesis. Here, we identify previously unknown pathways required for antigen (Ag)-specific tolerogenic immune-modifying particle/Cour nanoparticle (TIMP/CNP)-induced tolerance. The data show that myeloid cells phagocytose CNPs, undergo apoptosis, and release oxidized DNA [8-hydroxy-2'-deoxyguanosine (8-OHG)]. Subsequently, Ag-specific CNP treatment increases the number of PD-L1+ cDC2 dendritic cells and the number of FoxP3+, CTLA-4+, PD-1+, and IL-10+ regulatory CD4+ T cells via a stimulator of interferon genes (STING)/interferon-α/β receptor (IFNAR)-dependent pathway. In addition, these same pathways were found to be required for both Ag-coupled apoptotic leukocyte-induced and Ag-coupled red blood cell treatment-induced CD4+ T cell tolerance. Together, these results show that Ag-specific tolerance induced by the presence of apoptotic cells, and by CNP-induced apoptosis, requires the STING/IFNAR pathway, thereby illustrating a previously unknown function of this pathway.