CD4+CD25+ T regulatory cells from FIV+ cats induce a unique anergic profile in CD8+ lymphocyte targets.

Background: Using the FIV model, we reported previously that CD4+CD25+ T regulatory (Treg) cells from FIV+ cats are constitutively activated and suppress CD4+CD25- and CD8+ T cell immune responses. In an effort to further explore Treg-mediated suppression, we asked whether Treg cells induce anergy through the alteration of production of cyclins, cyclin-dependent kinases and their inhibitors.

Results: Lymphocytes were obtained from control or FIV+ cats and sorted by FACS into CD4+CD25+ and CD8+ populations.

CD4(+)CD25(+) T regulatory cells inhibit CD8(+) IFN-gamma production during acute and chronic FIV infection utilizing a membrane TGF-beta-dependent mechanism.

CD8(+) lymphocytes are critical to the control and elimination of viral pathogens. Impaired CD8(+) responses are well recognized in lentiviral infections; however, the mechanisms underlying CD8(+) impairment remain elusive. Using the feline immunodeficiency virus (FIV) model for human AIDS, we reported previously that CD4(+)CD25(+) Treg cells in both the acute and long-term, asymptomatic phase of infection are constitutively activated and suppress CD4(+)CD25(-) T cell responses.

CD4+CD25+ regulatory T cells are infected and activated during acute FIV infection.

HIV-induced AIDS may be mediated by the activation of immunosuppressive CD4+CD25+ T regulatory cells (Treg cells). Treg cells have been shown to regulate CD4+ and CD8+ immune responses to HIV and FIV antigens in vitro. We tested the hypothesis that Treg cells become infected and activated during the acute infection with FIV leading to the suppression of CD4+ T helper cell responses.

Lentivirus-induced immune dysregulation.

FIV/HIV infections are associated with an early robust humoral and cellular anti-viral immune response followed by a progressive immune suppression that eventually results in AIDS. Several mechanisms responsible for this immune dysfunction have been proposed including cytokine dysregulation, immunologic anergy and apoptosis, and inappropriate activation of immune regulatory cells. Studies on FIV infection provide evidence for all three.

Transforming growth factor-beta/transforming growth factor-betaRII signaling may regulate CD4+CD25+ T-regulatory cell homeostasis and suppressor function in feline AIDS lentivirus infection.

We have reported that CD4+CD25+ T-regulatory (Treg) cells are fully activated for suppressor function in feline immunodeficiency virus (FIV)-infected cats. Studies have suggested that surface transforming growth factor-beta (TGFbeta; membrane TGFbeta [mTGFbeta]) is a feature of activated CD4+CD25+ Treg cells and may play a role in Treg homeostasis and suppressor function. Herein, we explore the role of TGFbeta in feline Treg homeostasis and suppressor function and what effect FIV infection of cats might have on these processes.

The role of CD4+CD25+ regulatory T cells in viral infections.

Many virus infections result in the suppression of one or more functions of the immune system. Multiple mechanisms have been proposed to explain viral-induced immunosuppression, including an imbalance in the cellular Th1/Th2 or cytokine profile, induction of anergy, depletion of effector cells and most recently the activation of CD4+CD25+ regulatory T (T reg) cells. CD4+CD25+ T reg cells are a subset of circulating CD4+ T cells with suppressive properties.

Different thresholds of T cell activation regulate FIV infection of CD4+CD25+ and CD4+CD25- cells.

Cellular activation plays an important role in retroviral replication. Previously, we have shown that CD4(+)CD25(+) T cells by the virtue of their partially activated phenotype represent ideal candidates for a productive feline immunodeficiency virus (FIV) infection. In the present study, we extended our previous observations with regard to FIV replication in CD4(+)CD25(+) and CD4(+)CD25(-) cells under different stimulation conditions.

Preferential feline immunodeficiency virus (FIV) infection of CD4+ CD25+ T-regulatory cells correlates both with surface expression of CXCR4 and activation of FIV long terminal repeat binding cellular transcriptional factors.

Previously, we have characterized feline CD4+ CD25+ T-regulatory (Treg) cells with regard to their immune regulatory properties and ability to support feline immunodeficiency virus (FIV) replication in vitro and in vivo. Our studies showed that while CD4+ CD25+ cells were capable of replicating FIV in the presence of interleukin-2 (IL-2) alone, CD4+ CD25- cells harbored a latent infection that required a strong mitogenic stimulus to activate virus replication. In the present study, we investigated the mechanisms governing the preferential replication of FIV in highly purified CD4+ CD25+ Treg cells compared to their CD4+ CD25+ counterparts.

Feline immunodeficiency virus envelope glycoprotein mediates apoptosis in activated PBMC by a mechanism dependent on gp41 function.

Feline Immunodeficiency Virus (FIV) is a lentivirus that causes immunodeficiency in cats, which parallels HIV-1-induced immunodeficiency in humans. It has been established that HIV envelope (Env) glycoprotein mediates T cell loss via a mechanism that requires CXCR4 binding. The Env glycoprotein of FIV, similar to HIV, requires CXCR4 binding for viral entry, as well as inducing membrane fusion leading to syncytia formation.

Failure of FIV-infected cats to control Toxoplasma gondii correlates with reduced IL2, IL6, and IL12 and elevated IL10 expression by lymph node T cells.

Increased susceptibility to intracellular pathogens in HIV-infected individuals and FIV-infected cats is attributed to a defective T-helper 1 (Th1) immune response. However, little is known about specific cytokine responses to secondary pathogens. To address this question, control and FIV-infected cats were challenged with Toxoplasma gondii, and lymph node cells analyzed for cytokine mRNA expression.

Spontaneous T cell apoptosis in feline immunodeficiency virus (FIV)-infected cats is inhibited by IL2 and anti-B7.1 antibodies.

Lymph node (LN) T cells from feline immunodeficiency virus (FIV)-infected cats have an increased expression of B7 co-stimulatory molecules as well as their ligand CTLA4, resembling an activation phenotype shown to induce anergy and apoptosis in activated T cells. In addition, LN T cells from FIV-infected cats also show increased spontaneous apoptosis compared to uninfected animals. The apoptosis observed in these animals occurs primarily in T cells expressing B7 and CTLA4, suggesting a role for B7 and CTLA4 interactions in the induction of anergy/apoptosis.

Feline immunodeficiency virus infection phenotypically and functionally activates immunosuppressive CD4+CD25+ T regulatory cells.

Disease progression of feline immunodeficiency virus (FIV) infection is characterized by up-regulation of B7.1 and B7.2 costimulatory molecules and their ligand CTLA4 on CD4(+) and CD8(+) T cells.

Preferential replication of FIV in activated CD4(+)CD25(+)T cells independent of cellular proliferation.

Studies attempting to identify reservoirs of HIV-1 latency have documented that the virus persists as both a latent and productive infection in subsets of CD4(+) cells. Reports regarding establishment of a stable HIV-1 infection in quiescent T cells in vitro, however, are controversial. In the present study, we investigated the susceptibility of naive and activated CD4(+) cell subsets (distinguished by differential expression of CD25) to feline immunodeficiency virus (FIV) infection, their ability to replicate the virus, and potentially act as a reservoir for virus persistence in infected animals.

Mechanism of feline immunodeficiency virus envelope glycoprotein-mediated fusion.

Feline immunodeficiency virus (FIV) shares remarkable homology to primate lentiviruses, human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). The process of lentiviral env glycoprotein-mediated fusion of membranes is essential for viral entry and syncytia formation. A detailed understanding of this phenomenon has helped identify new targets for antiviral drug development.

B7+CTLA4+ T cells engage in T-T cell interactions that mediate apoptosis: a model for lentivirus-induced T cell depletion.

Apoptosis in lymph node (LN) T cells of feline immunodeficiency virus (FIV)-infected cats is associated with cells co-expressing B7.1 and B7.2 costimulatory molecules, and their ligand CTLA4.

Evaluation of T lymphocytes in captive african lions (Panthera leo) infected with feline immunodeficiency virus.

Objective: To determine whether FIV infection in captive African lions is associated with changes in immune cell variables similar to those detected in domestic cats infected with FIV.

Animals: 5 captive African lions naturally infected with FIV (FIV+) and 5 lions not infected with FIV (FIV-).

Procedure: Peripheral blood samples were collected from FIV+ lions during annual examinations conducted during a 7-year period and at a single time point from the FIV- lions.

Evaluation of FIV protein-expressing VEE-replicon vaccine vectors in cats.

Venezuelan equine encephalitis (VEE) virus-replicon particles (VRP) were used to generate feline immunodeficiency virus (FIV) Gag- and ENV-expressing vaccine vectors. Serum and mucosal FIV-specific antibody was detected in cats immunized subcutaneously, once monthly for 5 months, with FIV-expressing VRP. Expansion of the CD8+ L-selectin negative phenotype and transient CD8+ noncytolytic suppressor activity were seen in cats immunized with FIV-expressing or control VRP.

Feline immunodeficiency virus infection is characterized by B7+CTLA4+ T cell apoptosis.

The B7.1 and B7.2 costimulatory molecules on antigen-presenting cells provide second signals for regulating T cell immune responses via CD28 and cytotoxic T lymphocyte antigen 4 (CTLA4) on T cells.

Polymorphic expression in the CD8alpha chain surface receptor of African lions (Panthera leo).

Free-ranging African lion (Panthera leo) peripheral blood mononuclear cells (PBMC) were examined using flow cytometry and antibodies developed for use in the domestic cat to determine if phenotypic changes occurred in lion lymphocytes as a result of feline immunodeficiency virus (FIV) infection. The percentage of CD8 cells from lion peripheral blood was considerably lower than in the domestic cat. Lions with elevated levels of CD8+ cells were typically infected with FIV, similar to observations in the domestic cat.