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

Abstract

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 Vβ4+ TCRs. We previously demonstrated that Vβ4+CD8+ T cells recognize an uncharacterized ligand expressed on latently infected B cells in an MHC-independent manner. The frequency of Vβ4+CD8+ T cells increases dramatically following the peak of viral latency in the spleen. In the current studies, we show that elevated Vβ4+CD8+ T cell levels are sustained long-term in persistently infected mice, apparently a consequence of continued ligand expression. In addition, we show that Vβ4+CD8+ T cells can acquire effector functions, including cytotoxicity and the capacity to secrete IFN-γ, although they have an atypical activation profile compared with well-characterized CD8+ T cells specific for conventional viral epitopes. The characteristics of Vβ4+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 Vβ4+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.