Therapeutic role of interferon-γ in experimental autoimmune encephalomyelitis is mediated through a tolerogenic subset of splenic CD11b+ myeloid cells

J Neuroinflammation. 2024 May 31;21(1):144. doi: 10.1186/s12974-024-03126-3.

Abstract

Cumulative evidence has established that Interferon (IFN)-γ has both pathogenic and protective roles in Multiple Sclerosis and the animal model, Experimental Autoimmune Encephalomyelitis (EAE). However, the underlying mechanisms to the beneficial effects of IFN-γ are not well understood. In this study, we found that IFN-γ exerts therapeutic effects on chronic, relapsing-remitting, and chronic progressive EAE models. The frequency of regulatory T (Treg) cells in spinal cords from chronic EAE mice treated with IFN-γ was significantly increased with no effect on Th1 and Th17 cells. Consistently, depletion of FOXP3-expressing cells blocked the protective effects of IFN-γ, indicating that the therapeutic effect of IFN-γ depends on the presence of Treg cells. However, IFN-γ did not trigger direct in vitro differentiation of Treg cells. In vivo administration of blocking antibodies against either interleukin (IL)-10, transforming growth factor (TGF)-β or program death (PD)-1, revealed that the protective effects of IFN-γ in EAE were also dependent on TGF-β and PD-1, but not on IL-10, suggesting that IFN-γ might have an indirect role on Treg cells acting through antigen-presenting cells. Indeed, IFN-γ treatment increased the frequency of a subset of splenic CD11b+ myeloid cells expressing TGF-β-Latency Associated Peptide (LAP) and program death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)-1-dependent manner. Furthermore, splenic CD11b+ cells from EAE mice preconditioned in vitro with IFN-γ and myelin oligodendrocyte glycoprotein (MOG) peptide exhibited a tolerogenic phenotype with the capability to induce conversion of naïve CD4+ T cells mediated by secretion of TGF-β. Remarkably, adoptive transfer of splenic CD11b+ cells from IFN-γ-treated EAE mice into untreated recipient mice ameliorated clinical symptoms of EAE and limited central nervous system infiltration of mononuclear cells and effector helper T cells. These results reveal a novel cellular and molecular mechanism whereby IFN-γ promotes beneficial effects in EAE by endowing splenic CD11b+ myeloid cells with tolerogenic and therapeutic activities.

Keywords: CD11b+ cells; Experimental autoimmune encephalomyelitis; Interferon-γ; Multiple sclerosis; Regulatory T cells; TGF-β.

MeSH terms

  • Animals
  • CD11b Antigen* / metabolism
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental* / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental* / immunology
  • Encephalomyelitis, Autoimmune, Experimental* / metabolism
  • Encephalomyelitis, Autoimmune, Experimental* / pathology
  • Female
  • Forkhead Transcription Factors / metabolism
  • Interferon-gamma* / metabolism
  • Mice
  • Mice, Inbred C57BL*
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Myelin-Oligodendrocyte Glycoprotein / toxicity
  • Myeloid Cells* / drug effects
  • Myeloid Cells* / immunology
  • Myeloid Cells* / metabolism
  • Peptide Fragments / pharmacology
  • Peptide Fragments / toxicity
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • Spleen* / immunology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Transforming Growth Factor beta / metabolism

Substances

  • Interferon-gamma
  • CD11b Antigen
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Transforming Growth Factor beta
  • Programmed Cell Death 1 Receptor
  • Itgam protein, mouse
  • Forkhead Transcription Factors
  • myelin oligodendrocyte glycoprotein (35-55)
  • Pdcd1 protein, mouse