Abstract:
:Long-term, persistent central nervous system inflammation is commonly seen following brain infection. Using a murine model of viral encephalitis (murine cytomegalovirus, MCMV) we have previously shown that post-encephalitic brains are maintained in an inflammatory state consisting of glial cell reactivity, retention of brain-infiltrating tissue-resident memory CD8+ T-cells, and long-term persistence of antibody-producing cells of the B-lineage. Here, we report that this neuroinflammation occurs concomitantly with accumulation and retention of immunosuppressive regulatory T-cells (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-diphtheria toxin receptor-GFP (Foxp3-DTR-GFP) transgenic mice, which upon administration of low-dose 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 (0-4 dpi) resulted in depletion of Tregs from the brain, exacerbation of encephalitis (i.e., increased presence of CD4+ and CD8+ T-cells), and chronic reactive phenotypes of resident glial cells (i.e., elevated MHC Class II as well as PD-L1 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-encephalitic neuroinflammation, and its associated long-term neurological sequelae in response to viral brain infection are modulated by the immunoregulatory properties of Tregs. GLIA 2015;63:1982-1996.
journal_name
Gliajournal_title
Gliaauthors
Lokensgard JR,Schachtele SJ,Mutnal MB,Sheng WS,Prasad S,Hu Sdoi
10.1002/glia.22868subject
Has Abstractpub_date
2015-11-01 00:00:00pages
1982-1996issue
11eissn
0894-1491issn
1098-1136journal_volume
63pub_type
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