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T Cell Reactivity during Infectious Mononucleosis and Persistent Gammaherpesvirus Infection in Mice¹

Emilio Flaño^*, Charles L. Hardy^2,, In-Jeong Kim^*, Claire Frankling^*, Michael A. Coppola^3,, Phuong Nguyen, David L. Woodland^* and Marcia A. Blackman^4,*

^* Trudeau Institute, Saranac Lake, NY 12983; and Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105

Intranasal infection of mice with murine gammaherpesvirus 68 causes a dramatic increase in numbers of activated CD8⁺ T cells in the blood, analogous in many respects to EBV-induced infectious mononucleosis in humans. In the mouse model, this lymphocytosis has two distinct components: an early, conventional virus-specific CD8⁺ T cell response, and a later response characterized by a dramatic increase among CD8⁺ T cells that bear V4⁺ TCRs. We previously demonstrated that V4⁺CD8⁺ T cells recognize an uncharacterized ligand expressed on latently infected B cells in an MHC-independent manner. The frequency of V4⁺CD8⁺ T cells increases dramatically following the peak of viral latency in the spleen. In the current studies, we show that elevated V4⁺CD8⁺ T cell levels are sustained long-term in persistently infected mice, apparently a consequence of continued ligand expression. In addition, we show that V4⁺CD8⁺ T cells can acquire effector functions, including cytotoxicity and the capacity to secrete IFN-, although they have an atypical activation profile compared with well-characterized CD8⁺ T cells specific for conventional viral epitopes. The characteristics of V4⁺CD8⁺ T cells (potential effector function, stimulation by latently infected B cells, and kinetics of expansion) suggested that this dominant T cell response plays a key role in the immune control of latent virus. However, Ab depletion and adoptive transfer studies show that V4⁺CD8⁺ T cells are not essential for this function. This murine model of infection may provide insight into the role of unusual populations of activated T cells associated with persistent viral infections.

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