GM-CSF is not required for EAE induction but contributes to both brain and spinal cord inflammation

Abstract

Abstract Myelin-specific CD4+ T cells initiate inflammation in the central nervous system during induction of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. CD4+ T cell pathogenesis has been attributed to the secretion of various cytokines, including IL-17, GM-CSF, and IFN-γ. The relative importance of these CD4+ cytokines in EAE has been the subject of numerous studies, and in C57BL/6 and B10.PL mice, GM-CSF production by T cells is required to induce EAE, while IL-17 and IFN-γ are not required. However, our studies in C3Heb/Fej mice do not support an essential role for GM-CSF in the induction of EAE. Our model is unique in that C3Heb/Fej mice develop brain inflammation in addition to the spinal cord inflammation seen in most other EAE models. We have previously shown that IL-17 is important for (and IFN-γ inhibits) neutrophil recruitment and parenchymal inflammation in the brain of these mice, while IFN-γ promotes spinal cord inflammation. We found that GM-CSF−/− T cells were capable of inducing brain and spinal cord inflammation in wildtype recipient mice. In IL-17RA−/− recipients, wildtype T cells induce intermediate levels of brain inflammation and normal spinal cord inflammation. However, when GM-CSF−/− T cells were transferred into IL-17RA−/− recipient mice, there was a complete loss of clinical signs of brain inflammation, and spinal cord inflammation was significantly reduced, indicating that GM-CSF contributes to both brain and spinal cord inflammation. These data reveal that GM-CSF, IL-17, and IFN-γ all influence inflammation in the brain and spinal cord in C3Heb/Fej mice; while none are required, coordinately these cytokines shape CNS inflammation.