The Therapeutic Role of IFN-γ in Experimental Autoimmune Encephalomyelitis is Mediated by Tolerogenic Subsets of Splenic CD11b+ Myeloid Cells

Research Background

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by demyelination and axonal damage in the central nervous system (CNS). Although the etiology of MS is unclear, both genetic and environmental factors play roles in breaking self-tolerance. MS is classified into two main clinical forms: relapsing-remitting (RR)-MS, characterized by acute neuroinflammation with varying degrees of recovery, and progressive MS, which manifests as chronic and irreversible neurological dysfunction. Researchers have extensively studied the immunopathological mechanisms of MS and developed therapeutic strategies using the animal model of experimental autoimmune encephalomyelitis (EAE). The EAE model is induced by immunizing with myelin-derived antigens and adjuvants, encompassing the induction and effector phases. During the induction phase, peripheral myeloid antigen-presenting cells (APCs) process and present myelin antigens to naive CD4+ T cells, inducing the production of interferon-gamma (IFN-γ)-secreting Th1 cells and interleukin (IL)-17-secreting Th17 cells. Subsequently, in the early effector phase, innate and adaptive immune cells, including Th1 and Th17 cells, migrate from the periphery to the CNS, leading to rapid and acute disease progression that results in chronic demyelination and axonal damage. Myeloid APCs play a crucial role in both MS and EAE by activating encephalitogenic T cells and sustaining neuroinflammation.

Research Process

Experimental Design

This study reviewed the protective effects of interferon-gamma (IFN-γ) on EAE, with particular focus on its therapeutic efficacy in alleviating chronic, relapsing-remitting, and chronic-progressive EAE models. The study found that treatment with IFN-γ in chronic EAE mouse models significantly increased the frequency of regulatory T (Treg) cells in the spinal cord. This increase was independent of the frequency of Th1 and Th17 cells. However, the protective effect of IFN-γ was abrogated by the removal of FOXP3-expressing cells, indicating that the therapeutic effect of IFN-γ depends on the presence of Treg cells. Interestingly, IFN-γ did not directly induce Treg cell differentiation in vitro. Through in vivo blocking antibodies, researchers discovered that the protective effect of IFN-γ in EAE also relies on TGF-β and PD-1, but not on IL-10.

Experimental Results

This work focused on how IFN-γ regulates immune responses at the molecular level and promotes disease immunomodulation. Specifically, it looked at the increased frequency of TGF-β latency-associated peptide (LAP) and programmed death-ligand 1 (PD-L1) in splenic CD11b+ myeloid cells induced via the signal transducer and activator of transcription (STAT)-1-dependent pathway. Furthermore, preconditioning with myelin oligodendrocyte glycoprotein (MOG) peptide in vitro and IFN-γ-induced splenic CD11b+ cells exhibited a tolerogenic phenotype and capacity, promoting the conversion of naive CD4+ T cells through TGF-β secretion. Notably, transferring splenic CD11b+ cells from IFN-γ-treated EAE mice to untreated recipient mice alleviated clinical symptoms of EAE and limited CNS infiltration of monocytes and effector helper T cells.

Conclusion

This study unveils a novel protective mechanism of IFN-γ in neuroinflammation, providing new insights into the contradictory roles of IFN-γ in EAE and MS.