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

Area of Science:

• Immunology
• Molecular Biology
• Nanotechnology

Background:

• CD4+ T cell-mediated autoimmune diseases involve autoreactive T cell infiltration and tissue damage.
• Existing methods for inducing tolerance have limitations.
• Understanding novel pathways for tolerance induction is critical for therapeutic development.

Purpose of the Study:

• To identify previously unknown pathways involved in antigen (Ag)-specific tolerogenic immune-modifying particle/Cour nanoparticle (CNP)-induced tolerance.
• To elucidate the mechanisms by which CNPs and apoptotic cells induce CD4+ T cell tolerance.

Main Methods:

• Treatment with Ag-specific CNPs and Ag-coupled apoptotic cells.
• Analysis of myeloid cell apoptosis and oxidized DNA release (8-hydroxy-2'-deoxyguanosine).
• Flow cytometry to quantify PD-L1+ cDC2 dendritic cells and regulatory CD4+ T cells (FoxP3+, CTLA-4+, PD-1+, IL-10+).
• Assessment of the role of the stimulator of interferon genes (STING)/interferon-α/β receptor (IFNAR) pathway.

Main Results:

• Myeloid cells phagocytosed CNPs, underwent apoptosis, and released oxidized DNA.
• Ag-specific CNP treatment increased PD-L1+ cDC2 cells and regulatory CD4+ T cells via a STING/IFNAR-dependent pathway.
• The STING/IFNAR pathway was essential for tolerance induced by both CNPs and Ag-coupled apoptotic cells/red blood cells.

Conclusions:

• The STING/IFNAR pathway plays a previously unrecognized role in Ag-specific CD4+ T cell tolerance.
• Both CNP-induced apoptosis and apoptotic cell presence require the STING/IFNAR pathway for tolerance induction.
• This finding opens new avenues for developing immunotherapies for autoimmune conditions.