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

## TL;DR

This study shows that the STING/IFNAR pathway is essential for inducing immune tolerance using nanoparticles or apoptotic cells, preventing harmful immune responses.

## Contribution

The study reveals a previously unknown role of the STING/IFNAR pathway in antigen-specific immune tolerance induced by nanoparticles and apoptotic cells.

## Key findings

- Myeloid cells phagocytose CNPs, undergo apoptosis, and release oxidized DNA.
- Ag-specific CNP treatment increases PD-L1+ cDC2 dendritic cells and regulatory CD4+ T cells via the STING/IFNAR pathway.
- The STING/IFNAR pathway is required for both CNP-induced and apoptotic cell-induced CD4+ T cell tolerance.

## Abstract

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.

STING/IFNAR is required for both antigen-specific biodegradable nanoparticle- and apoptotic cell–induced immune tolerance in vivo.