Regulation of brain-derived T cells during acute central nervous system inflammation.
The unique immunologic environment of the central nervous system (CNS) regulates most local inflammatory responses. In some circumstances, however, immune-mediated injury to the brain can occur. To understand how lymphocytes are regulated within the CNS during an inflammatory response that does not produce immunopathology, we have studied T cells isolated from the brains of mice with Sindbis virus (SV) encephalitis. Even though they express activation markers, these T cells are arrested in the cell cycle and do not proliferate in vitro. Altered phosphorylation of the retinoblastoma gene product, a critical cell cycle regulator, appears to mediate this effect. Furthermore, while brain-derived T cells generate IFN-gamma, IL-4, and IL-10, these T cells are deficient in IL-2 production compared with peripheral T cells. This pattern of cytokine production occurs in cells that do not activate NF-kappaB normally. When T cells producing both IL-2 and IFN-gamma are adoptively transferred into SV-infected mice, some of these cells traffic into the brain. Those that enter the brain selectively down-regulate IL-2 production over time. Since normal brain lipids can inhibit IL-2 production and T cell proliferation in vitro, these substances may mediate these same effects in vivo. Collectively, these data show that the local environment of the CNS during SV encephalitis exerts a complex regulatory effect on T cells that are recruited into the brain. We speculate that this effect serves to prevent excessive local T cell reactivity. Whether and how this regulation might fail in the setting of autoimmune neurologic disease remains to be explored.
Irani
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Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Lin
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KI
Griffin
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DE
D000208:Acute Disease; D019264:Adoptive Transfer; D018354:Alphavirus Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D001923:Brain Chemistry / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D018792:Encephalitis, Viral / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000172:deficiency / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D012845:Sindbis Virus / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
D016207:Cytokines; D016328:NF-kappa B; D016160:Retinoblastoma Protein