Gammaherpesvirus Persistence Alters Key CD8 T-Cell Memory Characteristics and Enhances Antiviral Protection

Abstract

In herpesvirus infections, the virus persists for life but is contained through T-cell-mediated immune surveillance. How this immune surveillance operates is poorly understood. Recent studies of other persistent infections have indicated that virus persistence is associated with functional deficits in the CD8 ؉ T-cell response. To test whether this is the case in a herpesvirus infection, we used a mutant murine gammaherpesvirus that is defective in its ability to persist in the host. By comparing the immune response to this virus with a revertant virus that can persist, we were able to dissect the changes in the antiviral CD8 ؉ T-cell response that are induced by virus persistence. Surprisingly, persistently infected mice controlled a secondary challenge infection more rapidly than nonpersistently infected mice, indicating enhanced rather than diminished effector functions. Consistent with this, virus-specific CD8 T cells from these mice exhibited faster upregulation of the cytotoxic mediator granzyme B. Another unexpected finding was that CD8 ؉ T cells from neither infection responded efficiently to homeostatic cytokines. The unresponsiveness of the memory cells from the nonpersistently infected mice appears to be linked to the prolonged replication of virus within the lungs. Other changes seen in different chronic infection models were also observed, such as changes in Bcl-2 levels, interleukin-2 production, and the immunodominance hierarchy. These data show persistence of gammaherpesvirus type 68 alters the properties of CD8 ؉ T cells and illustrates that immune surveillance does not require CD8 T cells with the same attributes as "classical" memory CD8 ؉ T cells.

Type I Interferon Signaling Enhances CD8+T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

“…As shown in Fig. 1A and B, wild-type (WT) and IFNAR1 Ϫ/Ϫ mice had similar early kinetics of expansion of CD8 ϩ T cells specific for these two viral epitopes, with expansion of p56-specific CD8 ϩ T cells preceding expansion of p79-specific CD8 ϩ T cells as previously described (18)(19)(20). However, IFNAR1 Ϫ/Ϫ mice had approximately 2-to 4-fold-higher levels of p56-specific CD8 ϩ T cells beginning at 16 dpi and as late as 46 dpi and approximately 2-to 3-fold-higher levels of p79-specific CD8…”

Control of Memory CD8+ T Cell Differentiation by CD80/CD86-CD28 Costimulation and Restoration by IL-2 during the Recall Response

“…6D). This was somewhat surprising since MHV-68-specific memory CD8 ϩ T cells have more frequent encounters with Ag and exhibit a more effector memory cell phenotype (41), and it has been shown in vitro that effector cells have lower requirements for costimulation (63).…”

“…MHV-68 establishes a low-level persistent infection and memory CD8 ϩ T cells specific for the virus exhibit unique characteristics distinct from that of memory cells in acute viral infections (41). We have previously reported that MHV-68 ORF61-specific memory CD8 ϩ T cells require CD28 costimulation to elicit a robust recall response (22).…”

Latent herpesvirus infection arms NK cells

“…Our experiments examining the arming of NK cells, as well as previous experiments that uncovered heightened resistance against Listeria monocytogenes during herpesvirus latency, 18 made use of the latency-defective MuHV-4 mutant O73.stop. This virus replicates to normal 22,28 or near-normal levels 23 during acute infection but is severely defective in its ability to persist in the latent state. NK-cell activation is equivalent for wild-type MuHV-4 and O73.stop during acute infection.…”