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.