Acute viral encephalitis requires rapid pathogen elimination without significant bystander tissue damage. In this article, we show that IL-10, a potent anti-inflammatory cytokine, is produced transiently at the peak of infection by CD8 T cells in the brains of coronavirus-infected mice. IL-10+CD8 and IL-10−CD8 T cells interconvert during acute disease, possibly based on recent Ag exposure. Strikingly, IL-10+CD8 T cells were more highly activated and cytolytic than IL-10−CD8 T cells, expressing greater levels of proinflammatory cytokines and chemokines, as well as cytotoxic proteins. Even though these cells are highly proinflammatory, IL-10 expressed by these cells was functional. Furthermore, IL-10 produced by CD8 T cells diminished disease severity in mice with coronavirus-induced acute encephalitis, suggesting a self-regulatory mechanism that minimizes immunopathological changes.

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Pathogen-specific Foxp3+ T reg cells can be identified on the basis of cytokine production, are detected in naive T cell populations, and exhibit suppressive ability toward effector T cells with the same antigen specificity.

b Chemokine (C-C motif) ligand 2 (CCL2), a chemoattractant for macrophages, T cells, and cells expressing CCR2, is upregulated during acute and chronic inflammation. CCL2 has been implicated in both proinflammatory and anti-inflammatory responses and has been suggested as a target for therapy in some inflammatory disorders. To examine the role of CCL2 during virus infection, we infected mice transgenically expressing CCL2 in the central nervous system (CCL2 Tg) with an attenuated neurotropic coronavirus (rJ2.2 strain of mouse hepatitis virus). Infection of wild-type mice with rJ2.2 results in mild acute encephalitis, followed by a nonlethal, chronic demyelinating disease. Proinflammatory innate and adaptive immune responses mediate virus clearance. In marked contrast, CCL2 Tg mice infected with rJ2.2 ineffectively cleared virus and rapidly succumbed to the infection. CCL2 Tg mice mounted a dysregulated immune response, characterized by augmented accumulation of regulatory Foxp3 ؉ CD4 ؉ T cells and of nitric-oxide-and YM-1-expressing macrophages and microglia, suggestive of mixed M1/M2 macrophage activation. Further, macrophages from infected CCL2 Tg brains relative to non-Tg controls were less activated/mature, expressing lower levels of major histocompatibility complex class II (MHC-II), CD86, and CD40. Collectively, these results show that persistent CCL2 overexpression establishes and sustains an immunological milieu that is both inflammatory and immunosuppressive and predisposes mice to a defective immune response to a minimally lethal virus.