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CD8⁺ T Lymphocytes Control Murine Cytomegalovirus Replication in the Central Nervous System of Newborn Animals¹

Glenn R. B. Bantug^*, Djurdijca Cekinovic, Russell Bradford, Thad Koontz, Stipan Jonjic and William J. Britt^2,*,,

^* Department of Microbiology, Department of Pediatrics, and Department of Neurobiology, University of Alabama at Birmingham, Alabama 35294; and Department of Embryology and Histology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia

Human CMV infection of the neonatal CNS results in long-term neurologic sequelae. To define the pathogenesis of fetal human CMV CNS infections, we investigated mechanisms of virus clearance from the CNS of neonatal BALB/c mice infected with murine CMV (MCMV). Virus titers peaked in the CNS between postnatal days 10–14 and infectious virus was undetectable by postnatal day 21. Congruent with virus clearance was the recruitment of CD8⁺ T cells into the CNS. Depletion of CD8⁺ T cells resulted in death by postnatal day 15 in MCMV-infected animals and increased viral loads in the liver, spleen, and the CNS, suggesting an important role for these cells in the control of MCMV replication in the newborn brain. Examination of brain mononuclear cells revealed that CD8⁺ T cell infiltrates expressed high levels of CD69, CD44, and CD49d. IE1₁₆₈-specific CD8⁺ T cells accumulated in the CNS and produced IFN- and TNF- but not IL-2 following peptide stimulation. Moreover, adoptive transfer of brain mononuclear cells resulted in decreased virus burden in immunodepleted MCMV-infected syngeneic mice. Depletion of the CD8⁺ cell population following transfer eliminated control of virus replication. In summary, these results show that functionally mature virus-specific CD8⁺ T cells are recruited to the CNS in mice infected with MCMV as neonates.

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 Grant HD 044721 (to W.J.B.).

² Address correspondence and reprint requests to Dr. William J. Britt, Department of Pediatrics, Children’s Hospital, Room 104 Harbor Building, 1600 7th Avenue South, University of Alabama at Birmingham, Birmingham, AL 35233. E-mail address: wbritt{at}peds.uab.edu

³ Abbreviations used in this paper: HCMV, human CMV; MCMV, murine CMV; PN, postnatal; IE1, immediate-early 1.

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