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Using a murine model of viral encephalitis (murine cytomegalovirus, MCMV) we have previously shown that post\u2010encephalitic brains are maintained in an inflammatory state consisting of glial cell reactivity, retention of brain\u2010infiltrating tissue\u2010resident memory CD8<jats:sup>+<\/jats:sup> T\u2010cells, and long\u2010term persistence of antibody\u2010producing cells of the B\u2010lineage. Here, we report that this neuroinflammation occurs concomitantly with accumulation and retention of immunosuppressive regulatory T\u2010cells (Tregs), and is exacerbated following their ablation. However, the extent to which these Tregs function to control neuroimmune activation following MCMV encephalitis is unknown. In this study, we used Foxp3\u2010diphtheria toxin receptor\u2010GFP (Foxp3\u2010DTR\u2010GFP) transgenic mice, which upon administration of low\u2010dose diphtheria toxin (DTx) results in the specific depletion of Tregs, to investigate their function. We found treatment with DTx during the acute phase of viral brain infection (0\u20134 dpi) resulted in depletion of Tregs from the brain, exacerbation of encephalitis (i.e., increased presence of CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T\u2010cells), and chronic reactive phenotypes of resident glial cells (i.e., elevated MHC Class II as well as PD\u2010L1 levels, sustained microgliosis, and increased glial fibrillary acidic protein (GFAP) expression on astrocytes) versus untreated, infected animals. This chronic proinflammatory environment was associated with reduced cognitive performance in spatial learning and memory tasks (Barnes Maze) by convalescent animals. These data demonstrate that chronic glial cell activation, unremitting post\u2010encephalitic neuroinflammation, and its associated long\u2010term neurological sequelae in response to viral brain infection are modulated by the immunoregulatory properties of Tregs. 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