MS and EAE are both associated with T cells secreting IFN-c (Th1 cells) and IL-17 (Th17 cells) which play complex, not fully understood roles in disease initiation and progression [2, 9] . In vivo and in vitro evidence indicates that suppression of encephalitogenic T cell proliferation within the CNS during EAE and activation of anti-inflammatory programs are in part mediated via astrocytes [4, 5] . Similar to astrocytes, IFN-c mediates both proand anti-inflammatory functions during autoimmune disease [10] . Early IFN-c induced effects are pro-inflammatory; IFN-c facilitates inflammatory cell access, shapes their composition, increases major histocompatibility complex (MHC) expression, contributes to macrophage and microglia activation, and initiates oligodendrocyte death [11] . Similarly, IFN-c mediated protection during EAE is also multifaceted [12] [13] [14] [15] . It acts as a negative regulator of neutrophil accumulation, Th17 cell activation, IL-1R signaling, protease secretion, and chemokine activity. It also inhibits proinflammatory cytokine secretion via induction of suppressor of cytokine secretion (SOCS) proteins, facilitates T cell apoptosis and protects oligodendrocytes via inducing endoplasmic reticulum (ER) stress responses [10, 11, 16, 17] . This highlights the critical role of a single mediator in both promoting disease but also limiting inflammatory mediated damage required to initiate repair cascades. Based on the gatekeeper functions of astrocytes and the diverse biological effects of IFN-c, we set out to determine how IFN-c signaling specifically to astrocytes influences CNS autoimmune disease. The results demonstrate that IFN-c signaling to astrocytes had no profound effects on initial disease progression, but played an essential protective role during the transition from acute to chronic disease. Clinical remission induced by IFN-c signaling to astrocytes coincided with reduced demyelination, axonal degeneration, and astrocyte activation. The IFN-c receptor is expressed ubiquitously; however, these data reveal astrocytes as the primary target and mediator of the well established antiinflammatory activity of IFN-c within the CNS.