GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis.
Multiple sclerosis (MS) is a CNS autoimmune disease believed to be triggered by T cells secreting Th1-specific proinflammatory cytokines, such as GM-CSF. In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), Th1 but not Th2 cells have been shown to induce disease; however, to date, no single encephalitogenic T cell-derived cytokine has been shown to be required for EAE onset. Because GM-CSF-deficient mice have been shown to be resistant to EAE following immunization with myelin self-Ag, we investigated the cellular source of the required GM-CSF and found that GM-CSF production by encephalitogenic T cells, but not CNS resident or other peripheral cells, was required for EAE induction. Furthermore, we showed that microglial cell activation, but not peripheral macrophage activation, was a GM-CSF-dependent process. Activation of microglial cells by the injection of LPS abrogated the GM-CSF requirement for EAE induction, suggesting that microglial cell activation is required for EAE onset. These data also demonstrate that GM-CSF is a critical Th1 cell-derived cytokine required for the initiation of CNS inflammation associated with EAE, and likely MS.
Ponomarev
Eugene D
ED
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201, USA.
Shriver
Leah P
LP
Maresz
Katarzyna
K
Pedras-Vasconcelos
Joao
J
Verthelyi
Daniela
D
Dittel
Bonnie N
BN
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D017628:Microglia / Q000276:immunology*; D009103:Multiple Sclerosis / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*
C408982:CPG-oligonucleotide; D016207:Cytokines; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor