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• NFAT5 haplodeficiency ameliorates EAE in female mice, but not in male mice. • NFAT5 haploinsufficiency increases Treg cell frequency in EAE only in the female CNS and spleen. • NFAT5 haplodeficiency reduces CD11c+ dendritic cell frequency in the spleens of both male and female EAE mice, but not in the CNS of either sex. • NFAT5 haplodeficiency reduces CD11c+CD8α+ dendritic cells in the female CNS, but rescue of CD11c+CD8α+ cells in the female CNS with Flt3L at peak EAE has no significant effect on EAE clinical course. Multiple sclerosis disproportionally affects women. The present study was undertaken to determine whether NFAT5 contributed to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, and if it did, whether the impact was sex associated. NFAT5 haplodeficiency reduced the disease severity only in female mice. This effect was associated with significant increases in frequency of T regulatory (Treg) cells in the CNS (from 1.45 ± 0.39% to 3.73 ± 0.94%) and spleen from (0.31 ± 0.06% to 0.94 ± 0.29%) without significantly affecting the CNS CD4+ subsets frequency. NFAT5 haploinsufficiency also significantly reduced the frequency of CD11c+CD8α+ dendritic cells in the female CNS. However, increase of their frequency in the CNS via intraperitoneal Flt3L injection at peak EAE had no significant effect on the disease courses. We conclude that NFAT5 contributes to pathogenesis of EAE in female mice, possibly through decreasing tissue specific frequency of Treg cells. [ABSTRACT FROM AUTHOR]