The role of tumor necrosis factor receptor 2 in experimental autoimmune encephalomyelitis

Abstract

Abstract Multiple sclerosis (MS) is an autoimmune neuroinflammatory disease that affects over 2 million people globally. HLA-DR2b is a major histocompatibility complex (MHC) locus in humans responsible for antigen-specific immune responses. HLA-DR2b (DRB1*15:01) is a major genetic risk factor for MS. Experimental autoimmune encephalomyelitis (EAE) is the animal model for MS and can provide insights into the mechanisms behind MS pathogenicity. Tumor necrosis factor receptor 2 (TNFR2) was suspected to control EAE severity by altering regulatory T cell (Treg) function and impairing remyelination. In the absence of TNFR2, mice expressing the human DR2b allele and lacking mouse MHC II develop progressive EAE upon adoptive transfer of myelin oligodendrocyte glycoprotein (MOG)-reactive CD4 T cells. These mice show altered Treg phenotype, including decreased expression of Helios, a marker of thymic Tregs, by splenic Tregs from DR2bΔR2 mice compared with DR2b mice. However, it remains unclear how the presence or absence of TNFR2 alters the expression of specific protective genes in both astrocytes and Tregs in the context of EAE. Using the DR2bΔR2 and DR2b mouse models, we investigated the impact of TNFR2 on protective astrocyte subsets and regulatory T cells by single-cell RNA sequencing (scRNA-seq) in the context of both active and adoptive transfer EAE. Our results elucidate mechanisms underlying the protective function TNFR2 via modulating astrocyte and regulatory T cell function in EAE. Our results may aid in the development of new treatments for MS. Supported by grant 1RO1NS117742 from the NIH/NINDS (T.G.F.) and by NIH/NIGMS RISE grant GM60655 (BB).