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A Novel Virus Carrier State to Evaluate Immunotherapeutic Regimens: Regulatory T Cells Modulate the Pathogenicity of Antiviral Memory Cells¹

Department of Immunology, Molecular and Integrative Neurosciences Department, and Harold L. Dorris Neurological Research Institute, Scripps Research Institute, La Jolla, CA 92037

Restrictions in the diversity of an adaptive immune repertoire can facilitate viral persistence. Because a host afflicted with an immune deficiency is not likely to purge a persistent infection using endogenous mechanisms, it is important to explore adoptive therapies to supplement the host with a functional immune defense. In this study, we describe a virus carrier state that results from introducing lymphocytic choriomeningitis virus (LCMV) into adult mice possessing a restricted T cell repertoire. On infection of these mice, LCMV establishes systemic persistence, and within the CNS the virus infects astrocytes (and later oligodendrocytes) rather than its traditional parenchymal target neurons. To determine whether LCMV could be purged from a novel target selection in the absence of an endogenous immune repertoire, we adoptively transferred virus-specific memory cells into adult carrier mice. The memory cells purged virus from the periphery as well as the CNS, but they induced fatalities not typically associated with adoptive immunotherapy. When the repertoire of the recipient mice was examined, a deficiency in natural regulatory T cells was noted. We therefore supplemented carrier mice with regulatory T cells and simultaneously performed adoptive immunotherapy. Cotransfer of regulatory T cells significantly reduced mortality while still permitting the antiviral memory cells to purge the persistent infection. These data indicate that regulatory T cells can be used therapeutically to lessen the pathogenicity of virus-specific immune cells in an immunodeficient host. We also propose that the novel carrier state described herein will facilitate the study of immunotherapeutic regimens.

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 Grants NS048866-01, MH062261-06, and AI070967-01 and a grant from The Burroughs Wellcome Fund (all to D.B.M.).

² Address correspondence and reprint requests to Dr. Dorian B. McGavern, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: mcgad{at}scripps.edu

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; tg, transgenic; i.c., intracerebral(ly); Arm, Armstrong; GFAP, glial fibrillary acidic protein; CNPase, 2',3'-cyclic nucleotide 3'-phosphodiesterase.