Table 1.
The protective effects of IFN-γ and IFN-γ-producing immune cells in EAE and MS.
Cell type | Experimental design | Effects of IFN-γ | Reference |
---|---|---|---|
Macrophages | In vitro culture of IFNGR-deficient PEC | IFN-γ induces PEC NO-expression inhibiting proliferation of splenocytes | (33) |
Neutrophils | Induced EAE in IFN-γ and IFNGR-deficient mice | IFN-γ restricts neutrophils infiltration in the brainstem and cerebellum primarily by regulating CXCL2 expression | (40–42) |
In vitro analysis of Gr1+ neutrophils sorted from CNS of mice with EAE | IFN-γ secreted by T cells induced NO production by Gr1+ neutrophils which inhibited T cell proliferation | (43) | |
Myeloid-derived suppressor cells (MDSCs) | Analysis of CD11b+ Gr1+ MDSC from EAE mice | IFN-γ secreted by activated T cells induced MDSC inhibiting CD4+ T cells proliferation by NO-dependent manner | (44) |
EAE mice treated with anti-IFN-γ | Anti-IFN-γ reduced MDSCs frequency and increased EAE severity | (45) | |
Natural killer cells (NK) | EAE mice treated with anti-IFN-γ | Decreased Th17-characteristic transcription factors expression due to modulation of microglia activation | (46) |
HINT1/Hsp70 protein complex from brains of PLP-sensitized SJL/J mice injected into congenic mice before immunization | Upregulated MHC class I peptide H60 expression, increased NK cell IFN-γ production, inhibited IL-17 production, and prevented EAE | (47–49) | |
Analysis of NK cell functionality in human PBMC | RRMS patients exhibit impaired response to IL-12 and severely diminished IFN-γ production in CD3−CD56brightCD16− NK cells | (50) | |
Invariant NKT cells | In vivo IFN-γ neutralization in αGalCer-treated mice with EAE. In vitro iNKT analysis | Increased production of IFN-γ, IL-4, and IL-10 by iNKT cells which mediated the suppression of Th17 cells and increased EAE regulation by MDSCs | (51–53) |
Dendritic cells (DC) | Transfer of IFN-γ treated DC into murine EAE models | Induced an incompletely mature DC phenotype and decreased disease severity and relapse frequency | (54) |
In vitro analysis of splenocytes isolated from WT and IFN-γ-deficient EAE mice | Induced DC IL-27 expression which inhibited Th9 cell differentiation and IL-9 production by Th9 and Th17 cells | (55) | |
CD4+ T lymphocytes | IFN-γ added to CD3-activated PBMC from chronic-progressive MS patients | Lymphocyte proliferation inhibition in an IFN-γ dose-dependent manner | (56) |
Analysis of IFN-γ deficient mice with EAE | Increased apoptosis and inhibited proliferation in vivo and ex vivo of CD4+CD44high T cells in spleen and CNS | (57) | |
Study of IFN-γ and IFNGR EAE deficient mice | Inhibited Th17 differentiation and IL-17 production | (31, 58–62) | |
IFN-γ deficient EAE mice treated with anti-IL-9 | Decreased Th9 differentiation and IL-9 production in vitro and in vivo in the CNS of mice with EAE | (55) | |
CD4+ T cells transfected with IFN-γ expressing vector transferred into EAE mice | Th1 IFN-γhighCD25−FOXP3− suppresses Th17 effector cells and decreased EAE severity | (63) | |
γδ T cells | EAE generated in bone marrow chimera with γδ and IFN-γ-deficient mice | γδ T cells promotes the expression of IFN-γ by T cells with a reduction of EAE severity | (64) |
CD4+ Tregs | In vitro addition of IFN-γ to mice and human CD4+CD25− T cell cultures. IFN-γ-converted Tregs injected into EAE mice | IFN-γ-converted Tregs inhibited T cell proliferation in mice and human cells. Administration of these cells ameliorated EAE severity | (65) |
CD8+ T lymphocytes | Transfer of MOG-induced CD8+ T cells from IFN-γ-deficient mice into wild-type mice before EAE induction | Amelioration of EAE severity mediated by CD8+ T cell IFN-γ production | (66) |
Analysis of CD8+LAP+ T cells from IFN-γ and IFNGR-deficient mice and transfer into EAE | IFN-γ production by CD8+LAP+ T cells inhibited T cell proliferation and reduced severity of EAE. | (67) | |
Vaccination with a TCR-derived peptide before EAE induction in WT and IFN-γ KO mice | Vaccination activates CD8αα+TCRαβ+ T cells and delayed EAE onset in an IFN-γ mediated fashion | (68–70) | |
Isolation of human and mice CD8+CD38high T cells. In vivo injection of CD8+CD38high into EAE mice | IFN-γ production by CD8+CD38high T cells inhibit T cell proliferation in human and mice. These cells decreased disease severity and delayed onset of EAE. | (71) | |
MS patients and EAE mice treated with Glatiramer acetate (GA) | GA increases CD8+ T proliferation and IFN-γ levels in MS and IDO and IFN-γ-producing CD8+ T cells in EAE | (72, 73) | |
B cells | IFN-γ treatment in early EAE stage in marmoset | Reduced plasma MOG-specific IgG levels | (35) |