Gammaherpesvirus Latency Differentially Impacts the Generation of Primary versus Secondary Memory CD8⁺T Cells during Subsequent Infection

Abstract

Unlike laboratory animals, humans are infected with multiple pathogens, including the highly prevalent herpesviruses. The purpose of these studies was to determine the effect of gammaherpesvirus latency on T cell number and differentiation during subsequent heterologous viral infections. Mice were first infected with murine gammaherpesvirus 68 (MHV68), a model of EpsteinBarr virus (EBV) infection, and then after latency was established, they were challenged with the Armstrong strain of lymphocytic choriomeningitis virus (LCMV). The initial replication of LCMV was lower in latently infected mice, and the maturation of dendritic cells was abated. Although the number of LCMV-specific effector CD8؉ T cells was not altered, they were skewed to a memory phenotype. In contrast, LCMV-specific effector CD4؉ T cells were increased in latently infected mice compared to those in mice infected solely with LCMV. When the memory phase was reached, latently infected mice had an LCMVspecific memory T cell pool that was increased relative to that found in singly infected mice. Importantly, LCMV-specific memory CD8؉ T cells had decreased CD27 and increased killer cell lectin-like receptor G1 (KLRG1) expression. Upon secondary challenge, LCMV-specific secondary effector CD8 ؉ T cells expanded and cleared the infection. However, the LCMV-specific secondary memory CD8 ؉ T cell pool was decreased in latently infected animals, abrogating the boosting effect normally observed following rechallenge. Taken together, these results demonstrate that ongoing gammaherpesvirus latency affects the number and phenotype of primary versus secondary memory CD8 ؉ T cells during acute infection. IMPORTANCE CD8 ؉ T cells are critical for the clearance of intracellular pathogens, including viruses, certain bacteria, and tumors. However, current models for memory CD8؉ T cell differentiation are derived from pathogen-free laboratory mice challenged with a single pathogen or vaccine vector. Unlike laboratory animals, all humans are infected with multiple acute and chronic pathogens, including the highly prevalent herpesviruses Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex viruses (HSV), and varicella-zoster virus (VZV). The purpose of these studies was to determine the effect of gammaherpesvirus latency on T cell number and differentiation during subsequent heterologous viral infections. We observed that ongoing gammaherpesvirus latency affects the number and phenotype of primary versus secondary memory CD8 ؉ T cells during acute infection. These results suggest that unlike pathogen-free laboratory mice, infection or immunization of latently infected humans may result in the generation of T cells with limited potential for long-term protection.

Sequential Infection with Common Pathogens Promotes Human-like Immune Gene Expression and Altered Vaccine Response

“…Possible mechanisms include chronic stimulation of innate immune responses that regulate adaptive immunity, antigenic mimicry, cross-reactive immune responses, altered antigen presentation and changes in differentiation of memory and naïve lymphocyte responses (Hensley et al, 2007; Oldstone, 2005; Selin et al, 2006; Stelekati et al, 2014; Stelekati and Wherry, 2012; Virgin, 2014; Virgin et al, 2009). Latent infection with the γ-herpesvirus used in our studies, MHV68, alters the number and phenotype of memory CD8+ T cells (Barton et al, 2014). Latent MCMV infection also results in profound alteration in the T cell compartment, leading to impaired naïve T cell function (Cicin-Sain et al, 2012), despite no increase in susceptibility to secondary challenge with influenza virus, West Nile virus, or vesicular stomatitis (Marandu et al, 2015).…”

Lifelong CMV infection improves immune defense in old mice by broadening the mobilized TCR repertoire against third-party infection

“…In some cases, the mechanism was shown to involve persistent activation of the innate immune system (42). Such effects were either not studied in aging (40,44) or were found to not affect immune responses in older adults (43).…”

Known unknowns: how might the persistent herpesvirome shape immunity and aging?

“…Mice infected with γMHV-68 (an EBV-like virus) or murine CMV show heterologous protection against subsequent bacterial infection [**47], although this effect appears to be transient, and has been attributed to higher proinflammatory cytokines in the host [48]. A similar approach has shown that γMHV-68+ mice subsequently infected with LCMV have impaired DC maturation, and altered T cell priming to skew the population toward memory rather than effector subsets [49]. In mouse models, infection with γMHV-68 exacerbates EAE (a model of Multiple Sclerosis) [50].…”