Murine gamma-herpesvirus 68 limits naturally occurring CD4+CD25+ T regulatory cell activity following infection

During microbial infections, naturally occurring CD4+CD25+ T regulatory cells can suppress protective host responses or they can limit pathogen-induced inflammatory responses. The particular role played by these cells seems to depend upon the infectious agent being investigated. Gamma-herpesviruses are efficacious pathogens which are well-known for their ability to induce lymphoproliferative disease and to establish latency in the host. However, no studies have investigated the importance of naturally occurring CD4+CD25+ T regulatory cells during infection with these viruses. Using the murine model of gamma-herpesvirus infection, murine gamma-herpesvirus 68 (gammaHV-68), we were surprised to find that levels of the CD4+CD25+ T regulatory cell transcript, FoxP3, continued to decrease as viral latency increased and as the leukocytosis phase of the disease progressed. Consistent with these results, the decrease in FoxP3 protein expression followed similar kinetics. Along with the reduced expression of this regulatory T cell marker, we also observed diminished CD4+CD25+ T regulatory cell activity in these cells isolated from gammaHV-68-infected animals. Dendritic cells infected in vitro with gammaHV-68 did not alter the ability of normal CD4+CD25+ regulatory T cells to limit the proliferation of CD4+ Th cells following stimulation. Taken together, these studies demonstrate a decreased presence and activity of CD4+CD25+ T regulatory cells during the mononucleosis-like phase of this viral infection. These alterations in naturally occurring T regulatory cell function may help to explain the dysregulation of the host's immune response which allows the uncontrolled expansion of leukocytes as viral latency is established.