Generation of reactive oxygen intermediates (ROI) following antigen receptor ligation is critical to promote cellular responses. However, the effect of antioxidant treatment on humoral immunity during a viral infection was unknown. Mice were infected with lymphocytic choriomeningitis virus (LCMV) and treated with Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), a superoxide dismutase mimetic, from days 0 to 8 postinfection. On day 8, at the peak of the splenic response in vehicle-treated mice, virus-specific IgM and IgG antibody-secreting cells (ASC) were decreased 22-and 457-fold in MnTBAP-treated animals. By day 38, LCMV-specific IgG ASC were decreased 5-fold in the bone marrow of drug-treated mice, and virus-specific antibodies were of lower affinity. Interestingly, antioxidant treatment had no effect on the number of LCMV-specific IgG memory B cells. In addition to decreases in ASC, MnTBAP treatment decreased the number of functional virus-specific CD4 ؉ T cells. The decreased numbers of ASC observed on day 8 in drug-treated mice were due to a combination of Bim-mediated cell death and decreased proliferation. Together, these data demonstrate that ROI regulate antiviral ASC expansion and have important implications for understanding the effects of antioxidants on humoral immunity during infection and immunization.A ntibodies are a critical component of the immune system's defense to infectious microorganisms. In order to initiate an antibody response to a pathogen, naïve B cells must first be activated through recognition of antigen by the B cell receptor (BCR). Following antigen stimulation, activated B cells enlist cognate CD4 ϩ T cell help to stimulate clonal expansion (1). Upon activation and proliferation, B cells embark on two distinct differentiation pathways (2). First, the initial production of antibody to a pathogen is accomplished through the differentiation of activated B cells into extrafollicular plasmablasts (3). These short-lived cells are essential in generating low-affinity antibodies early during the infection. However, to generate long-lived humoral immunity, activated B cells must migrate to the germinal center, undergo affinity maturation by somatic hypermutation, and undergo isotype switching to produce memory B cells or antibody-secreting plasma cells (ASC) (3). Memory B cells are long-lived and rapidly respond to pathogen re-encounter by proliferating and differentiating into ASC (4). High-affinity, long-lived ASC migrate to the bone marrow, where they continuously secrete antibody and persist for a year or more in mice (5) and decades in humans (6). Therefore, determining the factors that modulate these pathways is critical not only for understanding the generation and maintenance of serological memory but also for optimizing vaccines and therapeutics for autoimmune disorders.Following antigen receptor ligation, reactive oxygen intermediates (ROI) are generated and required for B cell function (7-9). Previous work has demonstrated that antioxidant treatment decreased lipo...

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.

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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 herpesvirus latency on T cell number and differentiation during subsequent heterologous viral infections. Mice were infected with murine Gammaherpesvirus 68 (MHV68), a model of Epstein-Barr infection, and then after latency was established, infected with the Armstrong strain of lymphocytic choriomeningitis virus (LCMV). This resulted in increased LCMV-specific effector CD4+ T cells compared to mice infected only with LCMV. Although the number of LCMV-specific effector CD8+ T cells was not altered, they were skewed to a memory phenotype. When the memory phase was reached, mice that were infected with both viruses had a memory T cell pool that was increased relative to that found in singly infected mice. Importantly, LCMV-specific memory CD8+ T cells had altered CD27 and KLRG1 expression. Upon secondary challenge the LCMV-specific effector CD8+ and CD4+ T cell pools expanded and cleared the infection. When the secondary memory pool was established, mice that were also infected with MHV68 had decreased numbers of LCMV-specific CD8+ T cells and these cells were skewed to an effector-memory phenotype. Taken together these results demonstrate that acute viral infection in the context of ongoing latency affects the number and phenotype of primary versus secondary memory CD8+ T cells.