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Journal of Virology, March 2008, p. 2130-2139, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.01762-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CD4 T Cells Contribute to Virus Control and Pathology following Central Nervous System Infection with Neurotropic Mouse Hepatitis Virus

Stephen A. Stohlman,^1,2,3*, David R. Hinton,² Beatriz Parra,^3, Roscoe Atkinson,² and Cornelia C. Bergmann^1,2,3,

Departments of Neurology,¹ Pathology,² Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California 90033³

Received 12 August 2007/ Accepted 12 December 2007

Replication of the neurotropic mouse hepatitis virus strain JHM (JHMV) is controlled primarily by CD8⁺ T-cell effectors utilizing gamma interferon (IFN-) and perforin-mediated cytotoxicity. CD4⁺ T cells provide an auxiliary function(s) for CD8⁺ T-cell survival; however, their direct contribution to control of virus replication and pathology is unclear. To examine a direct role of CD4⁺ T cells in viral clearance and pathology, pathogenesis was compared in mice deficient in both perforin and IFN- that were selectively reconstituted for these functions via transfer of virus-specific memory CD4⁺ T cells. CD4⁺ T cells from immunized wild-type, perforin-deficient, and IFN--deficient donors all initially reduced virus replication. However, prolonged viral control by IFN--competent donors suggested that IFN- is important for sustained virus control. Local release of IFN- was evident by up-regulation of class II molecules on microglia in recipients of IFN- producing CD4⁺ T cells. CD4⁺ T-cell-mediated antiviral activity correlated with diminished clinical symptoms, pathology, and demyelination. Both wild-type donor CD90.1 and recipient CD90.2 CD4⁺ T cells trafficked into the central nervous system (CNS) parenchyma and localized to infected white matter, correlating with decreased numbers of virus-infected oligodendrocytes in the CNS. These data support a direct, if limited, antiviral role for CD4⁺ T cells early during acute JHMV encephalomyelitis. Although the antiviral effector mechanism is initially independent of IFN- secretion, sustained control of CNS virus replication by CD4⁺ T cells requires IFN-.

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* Corresponding author. Mailing address: Department of Neurosciences NC30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: (216) 445-9796. Fax: (216) 444-7927. E-mail: stohlms2{at}ccf.org

Published ahead of print on 19 December 2007.

Present address: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.

Present address: Department of Microbiology, Universidad del Valle, Cali, Colombia.

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Journal of Virology, March 2008, p. 2130-2139, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.01762-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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