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Costimulation Requirements for Antiviral CD8⁺ T Cells Differ for Acute and Persistent Phases of Polyoma Virus Infection¹

Christopher C. Kemball^2,*, Eun D. Han Lee^2,, Eva Szomolanyi-Tsuda, Thomas C. Pearson, Christian P. Larsen and Aron E. Lukacher^3,*

^* Department of Pathology and Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322; and Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655

The requirement for costimulation in antiviral CD8⁺ T cell responses has been actively investigated for acutely resolved viral infections, but it is less defined for CD8⁺ T cell responses to persistent virus infection. Using mouse polyoma virus (PyV) as a model of low-level persistent virus infection, we asked whether blockade of the CD40 ligand (CD40L) and CD28 costimulatory pathways impacts the magnitude and function of the PyV-specific CD8⁺ T response, as well as the humoral response and viral control during acute and persistent phases of infection. Costimulation blockade or gene knockout of either CD28 or CD40L substantially dampened the magnitude of the acute CD8⁺ T cell response; simultaneous CD28 and CD40L blockade severely depressed the acute T cell response, altered the cell surface phenotype of PyV-specific CD8⁺ T cells, decreased PyV VP1-specific serum IgG titers, and resulted in an increase in viral DNA levels in multiple organs. CD28 and CD40L costimulation blockade during acute infection also diminished the memory PyV-specific CD8⁺ T cell response and serum IgG titer, but control of viral persistence varied between mouse strains and among organs. Interestingly, we found that CD28 and CD40L costimulation is dispensable for generating and/or maintaining PyV-specific CD8⁺ T cells during persistent infection; however, blockade of CD27 and CD28 costimulation in persistently infected mice caused a reduction in PyV-specific CD8⁺ T cells. Taken together, these data indicate that CD8⁺ T cells primed within the distinct microenvironments of acute vs persistent virus infection differ in their costimulation requirements.

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