GFAPcR1D and wt mice were compared at the peak of acute disease to determine if IFN-c signaling altered astrocyte activation or CNS inflammation. Astrocyte hypertrophy and GFAP expression ( Fig. 1B) were similar in both groups, indicating no overt effects of IFN-c on initial astrocyte reactivity. Furthermore, neither the extent of inflammation nor the anatomic distribution of inflammatory cells was altered (Fig. 1B) . Flow cytometry confirmed no difference in the overall extent of CD45 hi inflammatory cells recruited into the CNS ( Fig. 2A) . Furthermore, percentages of CD4 + T cells ( Fig. 2A) , CD8 + T cells and macrophages within the infiltrates were also similar (Fig. 3) . In contrast to the association between increased EAE severity and neutrophil accumulation in the global absence of IFN-c [14, 15] , only a small percentage of neutrophils were identified in the CNS of both groups by flow cytometry (Fig. 3) ; their low presence was confirmed by the inability to identify cells with the characteristic morphology of neutrophils in the brain by histopathology (Fig. 1B) . The absence of increased neutrophils in the CNS of GFAPcR1D mice during acute disease suggested that clinical disease was aggravated by a mechanism distinct from global IFN-c deficiency. In addition to the similar frequency of CD4 + T cells in the brains of the two groups ( Fig. 2A) , myelin oligodendrocyte glycoprotein (MOG) reactive CD4 + T cells secreting IFN-c were also similar ( Fig. 2B ). By contrast, MOG specific CD4 + T cells secreting IL-17 ( Fig. 2B ) and Foxp3 + regulatory CD4 + T cells (Tregs) were decreased in GFAPcR1D mice compared to wt mice (Fig. 2C) . Reduced Th17 and Tregs may be attributed to increased IFN-c [10, 16] . Alternatively, as IFN-c is protective in EAE [12] [13] [14] [15] , increased disease severity may reflect reduced bioavailable IFN-c due to sequestration of IFN-c binding to the dominant negative receptor. However, measurement of IFN-c in cell free supernatants derived from dissociated brains at the peak of acute disease demonstrated protein levels of 2.160.2 ng/brain in wt mice versus 3.660.5 ng/brain in GFAPcR1D mice (n = 3; p,0.05). As overall frequencies of MOG reactive CD4 + T cells secreting IFN-c were similar, increased IFN-c in the brains of GFAPcR1D mice suggested enhanced secretion at the cellular level. Although a contribution of NK or CD8 T cells could not be excluded, these potential sources of IFN-c were unlikely due to their low frequencies (NK ,5% and CD8 + T cells , 5%, see Fig. 3 ) and their equivalent frequencies in the wt and GFAPcR1D mice. Furthermore, reduced Th17 cell and Treg frequencies were consistent with suppression of these populations due to elevated IFN-c [10, 16, 20] .