Murine γ-Herpesvirus 68 Limits Naturally Occurring CD4+CD25+ T Regulatory Cell Activity following Infection

Abstract

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. γ-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 γ-herpesvirus infection, murine γ-herpesvirus 68 (γHV-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 γHV-68-infected animals. Dendritic cells infected in vitro with γHV-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.

NK Cells Lyse T Regulatory Cells That Expand in Response to an Intracellular Pathogen

“…Murine gamma-herpesvirus 68 infection reduces Treg numbers and inhibits their function, although the underlying mechanisms are undefined (40). The human T cell lymphotropic virus type I-associated virus-encoded tax protein inhibits Foxp3 expression and suppressor function (41).…”

Murine Gammaherpesvirus-68 Infection Alters Self-Antigen Presentation and Type 1 Diabetes Onset in NOD Mice

“…Ag-specific regulatory T cells have long been implicated in dampening down inflammatory responses by reducing CD4 ϩ T cell activation; recent publications have demonstrated that MHV-68 can limit CD4 ϩ CD25 ϩ activity and decrease Foxp3 expression in splenic CD4 ϩ T cells (21). We therefore analyzed changes in the Foxp3 expression of transferred CFSE-labeled BDC2.5NOD CD4 ϩ T cells and of endogenous CD4 ϩ T cells and quantified the numbers of CD4 ϩ regulatory T cells within the PLN of MHV-68 infected and uninfected NOD mice.…”

Infection with murine gammaherpesvirus 68 exacerbates inflammatory bowel disease in IL-10-deficient mice

“…Virus stock was prepared by infecting BHK-21 cells [American Type Culture Collection (ATCC), Rockville, MD; CCL-10) with HV-68 at a low multiplicity of infection, followed by isolation of virus as previously described [31][32][33][34][35][36]. Replicating virus present in viral stocks was quantified using serial dilutions on NIH-3T3 cell (ATCC CRL 1658) monolayers.…”

“…Intranasal inoculations with HV-68 were performed as previously described [31][32][33][34][35][36]. Briefly, mice were anesthetized and allowed to aspirate, via the nasal passages, 20 ml of inoculum containing 6,000 plaque-forming units of HV-68.…”

“…Murine gammaherpesvirus 68 (HV-68) has been used as a mouse model for EBV and human herpesvirus 8 infections [27][28][29][30] and is the only well-characterized rodent model for studying gammaherpesviruses. Upon intranasal or oral inoculation in mice [31][32][33][34][35][36], there is a productive infection of epithelial cells, followed by infection of B lymphocytes, and also macrophages and dendritic cells. A marked leukocytosis (i.e., mononucleosis) and splenomegaly occur, which peak around days 15-20 postinfection.…”