Anthony M. Byers

Cutting Edge: Rapid In Vivo CTL Activity by Polyoma Virus-Specific Effector and Memory CD8+ T Cells

For viruses that establish persistent infection, continuous immunosurveillance by effector-competent antiviral CD8+ T cells is likely essential for limiting viral replication. Although it is well documented that virus-specific memory CD8+ T cells synthesize cytokines after short term in vitro stimulation, there is limited evidence that these T cells exhibit cytotoxicity, the dominant antiviral effector function. Here, we show that antiviral CD8+ T cells in mice acutely infected by polyoma virus, a persistent mouse pathogen, specifically eliminate viral peptide-pulsed donor spleen cells within minutes after adoptive transfer and do so via a perforin-dependent mechanism. Antiviral memory CD8+ T cells were similarly capable of rapidly mobilizing potent Ag-specific cytotoxic activity in vivo. These findings strongly support the concept that a cytotoxic effector-memory CD8+ T cell population operates in vivo to control this persistent viral infection.

In vitro stimulation of human influenza-specific CD8+ T cells by dendritic cells pulsed with an influenza virus-like particle (VLP) vaccine.

The purpose of this in vitro study was to determine if a virus-like particle (VLP) influenza vaccine stimulated human CD8(+) T cells in a dendritic cell (DC): T cell co-culture system. VLP-pulsed DCs were co-cultured with autologous CD8(+) T cells from five donors. Functional CD8(+) T cells were detected via cell surface and intracellular cytokine staining. T cells from four of the five donors showed >or=2-fold increase over background in the % activated CD8(+) cells. These results indicate that the influenza VLP vaccine can stimulate CD8(+) T cells via DC antigen presentation, likely through the MHC-I pathway, thus broadening the immunological response induced by this promising influenza vaccine.

CD94/NKG2A expression is associated with proliferative potential of CD8 T cells during persistent polyoma virus infection.

Memory CD8 T cells comprise a critical component of durable immunity because of their capacity to rapidly proliferate and exert effector activity upon Ag rechallenge. During persistent viral infection, memory CD8 T cells repetitively encounter viral Ag and must maintain a delicate balance between limiting viral replication and minimizing immunopathology. In mice infected by polyoma virus, a natural mouse pathogen that establishes long-term persistent infection, the majority of persistence-phase antiviral CD8 T cells express the inhibitory NK cell receptor CD94/NKG2A. In this study, we asked whether CD94/NKG2A expression is associated with Ag-specific recall of polyoma virus-specific CD8 T cells. During the persistent phase of infection, polyoma virus-specific CD8 T cells that express CD94/NKG2A were found to preferentially proliferate; this proliferation was dependent on cognate Ag both in vitro and in vivo. In addition, CD94/NKG2A+ polyoma-specific CD8 T cells have a markedly enhanced capacity to produce IL-2 upon ex vivo Ag stimulation compared with CD94/NKG2A− polyoma-specific CD8 T cells. Importantly, CD94/NKG2A+ anti-polyoma virus CD8 T cells appear to be essential for Ag-specific recall responses in mice persistently infected by polyoma virus. Because of its higher proliferative potential and capacity to produce IL-2, we propose that the CD94/NKG2A+ subpopulation represents a less differentiated state than the CD94/NKG2A− subpopulation. Identification of proliferation-competent subpopulations of memory CD8 T cells should prove valuable in designing therapeutic vaccination strategies for persistent viral infections.

Persistence of viral infection despite similar killing efficacy of antiviral CD8(+) T cells during acute and chronic phases of infection.

Why some viruses establish chronic infections while others do not is poorly understood. One possibility is that the hosts immune response is impaired during chronic infections and is unable to clear the virus from the host. In this report, we use a recently proposed framework to estimate the per capita killing efficacy of CD8(+) T cells, specific for the polyoma virus (PyV), which establishes a chronic infection in mice. Surprisingly, the estimated per cell killing efficacy of PyV-specific effector CD8(+) T cells during the acute phase of the infection was very similar to the efficacy of effector CD8(+) T cells specific to lymphocytic choriomeningitis virus (LCMV-Armstrong), which is cleared from the host. Our results suggest that persistence of PyV does not result from the generation of an inefficient PyV-specific CD8(+) T cell response, and that other host or viral factors are responsible for the ability of PyV to establish chronic infection.

Regulation of antiviral CD8+ T cells by inhibitory natural killer cell receptors.

Recent evidence indicates that CD8(+) T cells express natural killer cell receptors that constrain the range and magnitude of their activities. For virus-specific CD8(+) T cells, upregulation of these receptors serves to control infection, while concurrently minimizing bystander pathology. Dysregulated expression of these receptors, however, may foster the establishment of persistent virus infection.