Maturation of circulating Ly6ChiCCR2+ monocytes by mannan-MOG induces antigen-specific tolerance and reverses autoimmune encephalomyelitis

• Published in: Frontiers in immunology 2022-09, Vol.13, p.972003-972003
• Main Authors: Dagkonaki, Anastasia, Papalambrou, Athina, Avloniti, Maria, Gkika, Areti, Evangelidou, Maria, Androutsou, Maria-Eleni, Tselios, Theodore, Probert, Lesley
• Format: Article
• Language: English
• Subjects: demyelination; Immunology; immunotherapy; MDSC; monocyte maturation; multiple sclerosis; PD-L1, Cre/loxP mouse
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.972003

Autoimmune diseases affecting the CNS not only overcome immune privilege mechanisms that protect neural tissues but also peripheral immune tolerance mechanisms towards self. Together with antigen-specific T cells, myeloid cells are main effector cells in CNS autoimmune diseases such as multiple sclerosis, but the relative contributions of blood-derived monocytes and the tissue resident macrophages to pathology and repair is incompletely understood. Through the study of oxidized mannan-conjugated myelin oligodendrocyte glycoprotein 35-55 (OM-MOG), we show that peripheral maturation of Ly6C hi CCR2 + monocytes to Ly6C hi MHCII + PD-L1 + cells is sufficient to reverse spinal cord inflammation and demyelination in MOG-induced autoimmune encephalomyelitis. Soluble intradermal OM-MOG drains directly to the skin draining lymph node to be sequestered by subcapsular sinus macrophages, activates Ly6C hi CCR2 + monocytes to produce MHC class II and PD-L1, prevents immune cell trafficking to spinal cord, and reverses established lesions. We previously showed that protection by OM-peptides is antigen specific. Here, using a neutralizing anti-PD-L1 antibody in vivo and dendritic cell-specific Pdl1 knockout mice, we further demonstrate that PD-L1 in non-dendritic cells is essential for the therapeutic effects of OM-MOG. These results show that maturation of circulating Ly6C hi CCR2 + monocytes by OM-myelin peptides represents a novel mechanism of immune tolerance that reverses autoimmune encephalomyelitis.