Astrocyte TAK1-mediated production of chemotactic cues are necessary for the localization of CD4+T cell in gray matter in an EAE model with severe neurodegeneration.

Abstract

Abstract Multiple sclerosis (MS) is a chronic neurological disease of the central nervous system that is driven by peripheral immune cell infiltration and glial cell activation. The pathological hallmark of MS is primary demyelination, but recent evidence suggests gray matter neuronal damage is a major component of the irreversible nature of the disease. While T cells are found in both gray and white matter of MS tissue, they are typically confined to the white matter of the most commonly used mouse model of MS, experimental autoimmune encephalitis (EAE). Thus, genesis of T cells in the gray matter during MS pathogenesis is poorly understood. In this study, we used a modified EAE model (Type-B EAE) that displays severe neuronal damage without disease remission to investigate the role of T cells in neurodegeneration. Using immunohistochemistry and confocal imaging, we show that CD4+ T cells migrate to the spinal cord gray matter with selective preference for the ventral horns. Compared to CD4+ T cells in white matter, gray matter-infiltrated CD4+ T cells were mostly immobile (indicative of cell–cell interactions) and can be seen interacting directly with neuronal bodies. T cell-specific deletion of CXCR2 significantly decreased CD4+ T cell infiltration into gray matter in Type-B EAE mice. Inhibition of astrocyte chemokine production such as CXCL1, which was heightened in gray matter of Type-B EAE mice, by astrocyte-specific deletion of TAK1 successfully prevented T cell migration into spinal cord gray matter and rescued neuronal damage and motor dysfunction in Type-B EAE mice. This is the first report report that identifies the mechanism by which encephalomyelitic CD4+ T cells migrate to spinal cord gray matter, which correlates with neuronal damage.