Shifting Hierarchies of Interleukin-10-Producing T Cell Populations in the Central Nervous System during Acute and Persistent

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 immuno-dominant 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 suggest