Scaffolded Antigens in Yeast Cell Particle Vaccines Provide Protection against Systemic Polyoma Virus Infection.

Background. U65, a self-aggregating peptide scaffold, traps fused protein antigens in yeast cells. Conversion to Yeast Cell Particle (YCP) vaccines by partial removal of surface mannoproteins exposes β-glucan, mediating efficient uptake by antigen-presenting cells (APCs).

NK cells and virus-related cancers.

Natural killer (NK) cells become activated during viral infections and can play roles in such infections by attacking virus-infected cells or by regulating adaptive immune responses. Experimental models suggest that NK cells may also have the capacity to restrain virus-induced cancers. Here, we discuss the seven viruses linked to human cancers and the evidence of NK cell involvement in these systems.

Long-lasting T cell-independent IgG responses require MyD88-mediated pathways and are maintained by high levels of virus persistence.

Unlabelled: Many viruses induce acute T cell-independent (TI) B cell responses due to their repetitive epitopes and the induction of innate cytokines. Nevertheless, T cell help is thought necessary for the development of long-lasting antiviral antibody responses in the form of long-lived plasma cells and memory B cells. We found that T cell-deficient (T cell receptor β and δ chain [TCRβδ] knockout [KO]) mice persistently infected with polyomavirus (PyV) had long-lasting antiviral serum IgG, and we questioned whether they could generate TI B cell memory.

Inflammatory cytokine-mediated evasion of virus-induced tumors from NK cell control.

Infections with DNA tumor viruses, including members of the polyomavirus family, often result in tumor formation in immune-deficient hosts. The complex control involved in antiviral and antitumor immune responses during these infections can be studied in murine polyomavirus (PyV)-infected mice as a model. We found that NK cells efficiently kill cells derived from PyV-induced salivary gland tumors in vitro in an NKG2D (effector cell)-RAE-1 (target cell)-dependent manner; but in T cell-deficient mice, NK cells only delay but do not prevent the development of PyV-induced tumors.

Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response.

IRF-5 is a transcription factor activated by toll like receptor (TLR)7 and TLR9 during innate immune responses. IRF-5 activates not only Type I IFN, but also inflammatory cytokines. Most importantly, a genetic variation in the IRF-5 gene shows a strong association with autoimmune diseases such as Lupus.

Virion assembly factories in the nucleus of polyomavirus-infected cells.

Most DNA viruses replicate in the cell nucleus, although the specific sites of virion assembly are as yet poorly defined. Electron microscopy on freeze-substituted, plastic-embedded sections of murine polyomavirus (PyV)-infected 3T3 mouse fibroblasts or mouse embryonic fibroblasts (MEFs) revealed tubular structures in the nucleus adjacent to clusters of assembled virions, with virions apparently "shed" or "budding" from their ends. Promyelocytic leukemia nuclear bodies (PML-NBs) have been suggested as possible sites for viral replication of polyomaviruses (BKV and SV40), herpes simplex virus (HSV), and adenovirus (Ad).

Rapid recruitment and activation of macrophages by anti-Gal/α-Gal liposome interaction accelerates wound healing.

Macrophages are pivotal in promoting wound healing. We hypothesized that topical application of liposomes with glycolipids that carry Galα1-3Galβ1-4GlcNAc-R epitopes (α-gal liposomes) on wounds may accelerate the healing process by rapid recruitment and activation of macrophages in wounds. Immune complexes of the natural anti-Gal Ab (constituting ∼1% of Ig in humans) bound to its ligand, the α-gal epitope on α-gal liposomes would induce local activation of complement and generation of complement chemotactic factors that rapidly recruit macrophages.

NK cells and gammadelta T cells mediate resistance to polyomavirus-induced tumors.

NK and gammadelta T cells can eliminate tumor cells in many experimental models, but their effect on the development of tumors caused by virus infections in vivo is not known. Polyomavirus (PyV) induces tumors in neonatally infected mice of susceptible strains and in adult mice with certain immune deficiencies, and CD8+ alphabeta T cells are regarded as the main effectors in anti-tumor immunity. Here we report that adult TCRbeta knockout (KO) mice that lack alphabeta but have gammadelta T cells remain tumor-free after PyV infection, whereas TCRbeta x delta KO mice that lack all T cells develop tumors.

p53 represses class switch recombination to IgG2a through its antioxidant function.

Ig class switch recombination (CSR) occurs in activated mature B cells, and causes an exchange of the IgM isotype for IgG, IgE, or IgA isotypes, which increases the effectiveness of the humoral immune response. DNA ds breaks in recombining switch (S) regions, where CSR occurs, are required for recombination. Activation-induced cytidine deaminase initiates DNA ds break formation by deamination of cytosines in S regions.

The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses.

Inflammasomes regulate the activity of caspase-1 and the maturation of interleukin 1beta (IL-1beta) and IL-18. AIM2 has been shown to bind DNA and engage the caspase-1-activating adaptor protein ASC to form a caspase-1-activating inflammasome. Using Aim2-deficient mice, we identify a central role for AIM2 in regulating caspase-1-dependent maturation of IL-1beta and IL-18, as well as pyroptosis, in response to synthetic double-stranded DNA.

Generation of protective T cell-independent antiviral antibody responses in SCID mice reconstituted with follicular or marginal zone B cells.

B cells generated in the bone marrow of adult mice enter the periphery as transitional B cells and subsequently differentiate into one of two phenotypically and functionally distinct subsets, marginal zone (MZ) or follicular (Fo) B cells. Recent reports indicate, however, that in response to environmental cues, such as lymphopenia, mature Fo B cells can change to display phenotypic markers characteristic of MZ B cells. Previously, we found that splenic B cells transferred to SCID mice responded to polyoma virus (PyV) infection with T cell-independent (TI) IgM and IgG secretion, reducing the viral load and protecting mice from the lethal effect of the infection.

Immunity to polyomavirus infection: the polyomavirus-mouse model.

A ubiquitous clinically silent murine pathogen, polyomavirus has enjoyed long-term co-evolution with the mouse, a highly tractable and genetically and immunologically informative small animal model. Thus, polyomavirus has provided a valuable experimental construct to decipher the host immune mechanisms that come into play to control systemic low-level persistent viral infections. Impaired immunosurveillance for infected cells puts the murine host at risk both to injury resulting from excessive direct virus cytolysis and development of virus-induced tumors.

Allogeneic differences in the dependence on CD4+ T-cell help for virus-specific CD8+ T-cell differentiation.

CD4(+) T-cell help enables antiviral CD8(+) T cells to differentiate into fully competent memory cells and sustains CD8(+) T-cell-mediated immunity during persistent virus infection. We recently reported that mice of C57BL/6 and C3H strains differ in their dependence on CD28 and CD40L costimulation for long-term control of infection by polyoma virus, a persistent mouse pathogen. In this study, we asked whether mice of these inbred strains also vary in their requirement for CD4(+) T-cell help for generating and maintaining polyoma virus-specific CD8(+) T cells.

The antiviral CD8+ T cell response is differentially dependent on CD4+ T cell help over the course of persistent infection.

Although many studies have investigated the requirement for CD4(+) T cell help for CD8(+) T cell responses to acute viral infections that are fully resolved, less is known about the role of CD4(+) T cells in maintaining ongoing CD8(+) T cell responses to persistently infecting viruses. Using mouse polyoma virus (PyV), we asked whether CD4(+) T cell help is required to maintain antiviral CD8(+) T cell and humoral responses during acute and persistent phases of infection. Though fully intact during acute infection, the PyV-specific CD8(+) T cell response declined numerically during persistent infection in MHC class II-deficient mice, leaving a small antiviral CD8(+) T cell population that was maintained long term.

MyD88 is required for the formation of long-term humoral immunity to virus infection.

Development of long-term humoral immunity is a major goal of vaccination, but the mechanisms involved in the formation of long-term Ab responses are still being determined. In this study, we identify a previously unknown requirement for MyD88, an adaptor molecule that mediates signals at most TLRs, for the generation of long-term humoral immunity during live virus infection. Polyoma virus-infected MyD88 knockout mice generated strong acute T cell-dependent antiviral IgM and IgG responses and developed germinal centers.

Dynamics and magnitude of virus-induced polyclonal B cell activation mediated by BCR-independent presentation of viral antigen.

Hypergammaglobulinemia and production of autoantibodies occur during many viral infections, and studies have suggested that viral antigen-presenting B cells may become polyclonally activated by CD4 T cells in vivo in the absence of viral engagement of the BCR. However, we have reported that CD4 cells in lymphocytic choriomengitis virus (LCMV)-infected mice kill adoptively transferred B cells coated with LCMV class II peptides. We report here that most of the surviving naïve B cells presenting class II MHC peptides undergo an extensive differentiation process involving both proliferation and secretion of antibodies.

T cell-independent and T cell-dependent immunoglobulin G responses to polyomavirus infection are impaired in complement receptor 2-deficient mice.

Polyomavirus (PyV) infection induces protective T cell-independent (TI) IgM and IgG antibody responses in T cell-deficient mice, but these responses are not generated by immunization with viral proteins or virus like particles. We hypothesized that innate signals contribute to the generation of isotype-switched antiviral antibody responses. We studied the role of complement receptor (CR2) engagement in TI and T cell-dependent (TD) antibody responses to PyV using CR2-deficient mice.

Role for TLR2 in NK cell-mediated control of murine cytomegalovirus in vivo.

Natural killer (NK) cells are essential for the early control of murine cytomegalovirus (MCMV) infection. Here, we demonstrate that toll-like receptor 2 (TLR2) plays a role in the NK cell-mediated control of MCMV. TLR2 knockout (KO) mice had elevated levels of MCMV in the spleen and liver on day 4 postinfection compared to C57BL/6 mice.

Costimulation requirements for antiviral CD8+ T cells differ for acute and persistent phases of polyoma virus infection.

The requirement for costimulation in antiviral CD8+ T cell responses has been actively investigated for acutely resolved viral infections, but it is less defined for CD8+ T cell responses to persistent virus infection. Using mouse polyoma virus (PyV) as a model of low-level persistent virus infection, we asked whether blockade of the CD40 ligand (CD40L) and CD28 costimulatory pathways impacts the magnitude and function of the PyV-specific CD8+ T response, as well as the humoral response and viral control during acute and persistent phases of infection. Costimulation blockade or gene knockout of either CD28 or CD40L substantially dampened the magnitude of the acute CD8+ T cell response; simultaneous CD28 and CD40L blockade severely depressed the acute T cell response, altered the cell surface phenotype of PyV-specific CD8+ T cells, decreased PyV VP1-specific serum IgG titers, and resulted in an increase in viral DNA levels in multiple organs.

Judging a virus by its cover.

The production of protective neutralizing antibodies occurs quickly in some viral infections but very slowly in others. In a new study, surface glycoproteins (the targets of neutralization) of 2 different viruses were genetically switched. Analysis of the neutralizing antibody response to each of the 2 parent and recombinant viruses in infected mice revealed that the speed of neutralizing antibody induction was intrinsically dependent on the surface glycoprotein and not the rest of the virus.

Mycoplasma infection induces a scleroderma-like centrosome autoantibody response in mice.

Development of autoantibodies to intracellular molecules is a universal feature of autoimmune diseases and parallels onset of chronic inflammatory pathology. Initiating antigens of disease-specific autoantibody responses are unknown. We previously showed that the major targets of autoantibodies in scleroderma are centrosomes, organelles involved in mitotic spindle organization.

Immunological memory to viral infections.

The purpose of immunological memory is to protect the host from reinfection, to control persistent infections, and, through maternal antibody, to protect the host's immunologically immature offspring from primary infections. Immunological memory is an exclusive property of the acquired immune system, where in the presence of CD4 T cell help, T cells and B cells clonally expand and differentiate to provide effector systems that protect the host from pathogens. Here we describe how T and B cell memory is generated in response to virus infections and how these cells respond when the host is infected again by similar or different viruses.

The resolution of relapsing fever borreliosis requires IgM and is concurrent with expansion of B1b lymphocytes.

The rate of pathogen clearance is a critical determinant of morbidity and mortality. We sought to characterize the immune response responsible for the remarkably rapid clearance of individual episodes of bacteremia caused by the relapsing fever bacterium, Borrelia hermsii. SCID or Rag(-/-) mice were incapable of resolving B.