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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0803085v1 183/6/3895    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Truong, P. Articles by McGavern, D. B. PubMed PubMed Citation Articles by Truong, P. Articles by McGavern, D. B.

Persistent Viral Infection Elevates Central Nervous System MHC Class I through Chronic Production of Interferons¹

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Persistence of even the stealthiest viruses can perturb immune function either to the benefit or detriment of the host. Lymphocytic choriomeningitis virus (LCMV) establishes lifelong, systemic persistence when introduced in utero or at birth. Despite a highly evolved host-pathogen relationship, LCMV cannot escape detection by the innate immune system, which results in chronic stimulation of the type 1 IFN pathway in adult carrier mice. In this study we demonstrate that IFN-β is chronically up-regulated in peripheral lymphoid and nonlymphoid tissues (but not the CNS) of mice persistently infected from birth with LCMV and that dendritic cells (DCs) represent at least one source of IFN-β. Interestingly, chronic stimulation of this innate pathway significantly elevated MHC class I expression in the CNS as well as the periphery. Elevated MHC I expression was dependent on IFN-β receptor but not MyD88-dependent signaling, as only genetic deletion of the former reduced MHC I to normal levels. An increase in circulating virus was also observed in the IFN-β receptor deficient carrier mice, signifying that type I IFN continually exerts anti-viral pressure during a LCMV carrier state. Finally, to determine whether heightened CNS MHC I could be therapeutically corrected, we purged LCMV carrier mice of their persistent infection using adoptive immunotherapy. This treatment significantly reduced CNS MHC I expression. Collectively, these data demonstrate that even a well adapted pathogen can chronically stimulate the innate immune system and consequently alter the expression of Ag presenting machinery in an immunologically specialized compartment like the CNS.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Intramural program as well as Grants AI070967-01, MH062261-06, a grant from The Burroughs Wellcome Fund, and The Ray Thomas Edwards Foundation (all to D.B.M.). L.G. was supported by a fellowship from Association pour la recherché sur la sclerose en plaques.

² Address correspondence and reprint requests to Dr. Dorian B. McGavern, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892. E-mail address: mcgavernd{at}mail.nih.gov

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; MHC I, MHC class I; DC, dendritic cell; DT, diphtheria toxin; CD11c-DTR, CD11c-DT receptor; C_T, threshold cycle.

⁴ The online version of this article contains supplemental material.