title: Shifting hierarchies of interleukin-10-producing T cell populations in the central nervous system during acute and persistent viral encephalomyelitis.
abstract: Interleukin-10 (IL-10) mRNA is rapidly upregulated in the central nervous system (CNS) following infection with neurotropic coronavirus and remains elevated during persistent infection. Infection of transgenic IL-10/green fluorescent protein (GFP) reporter mice revealed that CNS-infiltrating T cells were the major source of IL-10, with minimal IL-10 production by macrophages and resident microglia. The proportions of IL-10-producing cells were initially similar in CD8(+) and CD4(+) T cells but diminished rapidly in CD8(+) T cells as the virus was controlled. Overall, the majority of IL-10-producing CD8(+) T cells were specific for the immunodominant major histocompatibility complex (MHC) class I epitope. Unlike CD8(+) T cells, a large proportion of CD4(+) T cells within the CNS retained IL-10 production throughout persistence. Furthermore, elevated frequencies of IL-10-producing CD4(+) T cells in the spinal cord supported preferential maintenance of IL-10 production at the site of viral persistence and tissue damage. IL-10 was produced primarily by the CD25(+) CD4(+) T cell subset during acute infection but prevailed in CD25(-) CD4(+) T cells during the transition to persistent infection and thereafter. Overall, these data demonstrate significant fluidity in the T-cell-mediated IL-10 response during viral encephalitis and persistence. While IL-10 production by CD8(+) T cells was limited primarily to the time of acute effector function, CD4(+) T cells continued to produce IL-10 throughout infection. Moreover, a shift from predominant IL-10 production by CD25(+) CD4(+) T cells to CD25(-) CD4(+) T cells suggests that a transition to nonclassical regulatory T cells precedes and is retained during CNS viral persistence.
authors.affiliation: Department of Neuroscience, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, NC30, Cleveland, OH 44195, USA.
authors.forename: Shweta S
authors.initials: SS
authors.lastname: Puntambekar
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
authors.forename: Carine
authors.initials: C
authors.lastname: Savarin
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Phares
authors.forename: Gabriel I
authors.initials: GI
authors.lastname: Parra
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
mesh_terms: D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology* / Q000821:virology; D002908:Chronic Disease; D018792:Encephalitis, Viral / Q000276:immunology / Q000821:virology; D004679:Encephalomyelitis / Q000276:immunology* / Q000821:virology; D016753:Interleukin-10 / Q000096:biosynthesis*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus / Q000276:immunology / Q000472:pathogenicity*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10