Beatrice M. Senn

Polyclonal and Specific Antibodies Mediate Protective Immunity against Enteric Helminth Infection

Anti-helminth immunity involves CD4+ T cells, yet the precise effector mechanisms responsible for parasite killing or expulsion remain elusive. We now report an essential role for antibodies in mediating immunity against the enteric helminth Heligmosomoides polygyrus (Hp), a natural murine parasite that establishes chronic infection. Polyclonal IgG antibodies, present in naive mice and produced following Hp infection, functioned to limit egg production by adult parasites. Comparatively, affinity-matured parasite-specific IgG and IgA antibodies that developed only after multiple infections were required to prevent adult worm development. These data reveal complementary roles for polyclonal and affinity-matured parasite-specific antibodies in preventing enteric helminth infection by limiting parasite fecundity and providing immune protection against reinfection, respectively. We propose that parasite-induced polyclonal antibodies play a dual role, whereby the parasite is allowed to establish chronicity, while parasite load and spread are limited, likely reflecting the long coevolution of helminth parasites with their hosts.

Deliberate removal of T cell help improves virus-neutralizing antibody production

The B cell response to lymphocytic choriomeningitis virus is characterized by a CD4+ T cell–dependent polyclonal hypergammaglobulinemia and delayed formation of virus-specific neutralizing antibodies. Here we provide evidence that, paradoxically, because of polyclonal B cell activation, virus-specific T cell help impairs the induction of neutralizing antibody responses. Experimental reduction in CD4+ T cell help in vivo resulted in potent neutralizing antibody responses without impairment of CD8+ T cell activity. These unexpected consequences of polyclonal B cell activation may affect vaccine strategies and the treatment of clinically relevant chronic bacterial, parasitic and viral infections in which hypergammaglobulinemia is regularly found.

Antiviral immune responses in gene-targeted mice expressing the immunoglobulin heavy chain of virus-neutralizing antibodies

Two gene-targeted immunoglobulin heavy chain transgenic mouse strains, TgH(KL25) and TgH(VI10), expressing neutralizing specificities for lymphocytic choriomeningitis virus and vesicular stomatitis virus, respectively, have been generated. Three days after lymphocytic choriomeningitis virus infection, TgH(KL25) mice showed a thymus-independent neutralizing IgM response followed by thymus-dependent (TD) IgG. In contrast, WT mice mounted only a TD IgG response around day 80. These observations indicated that not only structural properties of the virus but also immunological parameters such as the frequency of B cells were indicative for the induction of thymus-independent versus TD Ig responses. Naïve vesicular stomatitis virusspecific Ig heavy chain transgenic mice displayed greatly elevated natural antibody titers. However, despite these high naïve titers, de novo activation of naïve CD4+ T and B cells was not blocked. Therefore, B cells giving rise to natural antibodies do not participate in virus-induced antibody responses.

Impaired antibody response causes persistence of prototypic T cell-contained virus.

CD8 T cells are recognized key players in control of persistent virus infections, but increasing evidence suggests that assistance from other immune mediators is also needed. Here, we investigated whether specific antibody responses contribute to control of lymphocytic choriomeningitis virus (LCMV), a prototypic mouse model of systemic persistent infection. Mice expressing transgenic B cell receptors of LCMV-unrelated specificity, and mice unable to produce soluble immunoglobulin M (IgM) exhibited protracted viremia or failed to resolve LCMV. Virus control depended on immunoglobulin class switch, but neither on complement cascades nor on Fc receptor γ chain or Fc γ receptor IIB. Cessation of viremia concurred with the emergence of viral envelope-specific antibodies, rather than with neutralizing serum activity, and even early nonneutralizing IgM impeded viral persistence. This important role for virus-specific antibodies may be similarly underappreciated in other primarily T cell–controlled infections such as HIV and hepatitis C virus, and we suggest this contribution of antibodies be given consideration in future strategies for vaccination and immunotherapy.

CXCR5-Dependent Seeding of Follicular Niches by B and Th Cells Augments Antiviral B Cell Responses

The chemokine receptor CXCR5 and its ligand CXCL13 define the structure of B cell follicles within secondary lymphoid organs. Here, we examined the impact of CXCR5 on antiviral B cell responses in vivo. CXCR5−/− mice showed a normal production of IgM and IgG acutely after infection with vesicular stomatitis virus (VSV) and developed VSV-specific germinal centers. However, impaired Ig class switch and Ab production were observed under conditions of limited availability of Ag (i.e., after immunization with nonreplicating viral particles or soluble Ag). Adoptive transfer of CXCR5-deficient, VSV-specific B and Th cells demonstrated that CXCR5 expression on both B and Th cells is required for an efficient Ig class switch. These experiments revealed that CXCR5 is critical for the coordinated interaction of antiviral T and B cells through its impact on initial B cell expansion and the recruitment of Ag-specific B and Th cells to germinal centers.

Dendritic Cell-Independent B Cell Activation During Acute Virus Infection: A Role for Early CCR7-Driven B-T Helper Cell Collaboration

This study provides a detailed spatiotemporal interaction analysis between B cells, Th cells, and dendritic cells (DC) during the generation of protective antiviral B cell immunity. Following vesicular stomatitis virus (VSV) infection, conditional ablation of CD11c-positive DC at the time-point of infection did not impair extrafollicular plasma cell generation and Ig class switching. In contrast, the generation of Th and B cell responses following immunization with recombinant VSV-glycoprotein was DC-dependent. Furthermore, we show that the CCR7-dependent interplay of the three cell-types is crucial for virus-neutralizing B cell responses in the presence of limiting amounts of Ag. An immediate event following VSV infection was the CCR7-mediated interaction of VSV-specific B and Th cells at the T cell-B cell zone border that facilitated plasma cell differentiation and Th cell activation. Taken together, these experiments provide evidence for a direct, CCR7-orchestrated and largely DC-independent mutual activation of Th cells and Ag-specific B cells that is most likely a critical step during early immune responses against cytopathic viruses.

Additive Effect of Neutralizing Antibody and Antiviral Drug Treatment in Preventing Virus Escape and Persistence

ABSTRACT Poorly cytopathic or noncytopathic viruses can escape immune surveillance and establish a chronic infection. Here we exploited the strategy of combining antiviral drug treatment with the induction of a neutralizing antibody response to avoid the appearance of neutralization-resistant virus variants. Despite the fact that H25 immunoglobulin transgenic mice infected with lymphocytic choriomeningitis virus mounted an early neutralizing antibody response, the virus escaped from neutralization and persisted. After ribavirin treatment of H25 transgenic mice, the appearance of neutralization-resistant virus was prevented and virus was cleared. Thus, the combination of virus-neutralizing antibodies and chemotherapy efficiently controlled the infection, whereas each defense line alone did not. Similar additive effects may be unexpectedly efficient and beneficial in humans after infections with persistent viruses such as hepatitis C virus and hepatitis B virus and possibly human immunodeficiency virus.

Long‐term maternal imprinting of the specific B cell repertoire by maternal antibodies

Maternal antibodies protect newborns whilst they are immunologically immature. This study shows that maternal antibodies can also shape the B cell repertoire of the offspring long after the maternal antibodies themselves become undetectable. VHDJH gene‐targeted (VI10) mice expressing a heavy chain specific for vesicular stomatitis virus (VSV) produce a 20‐fold increased spontaneous titer of VSV‐neutralizing antibodies. When transferred from mother to offspring, these antibodies prevented accumulation of Ag‐specific transitional typeu20042 and marginal zone B cells with an activated phenotype and favored selection to the B cell follicles. This effect was B cell‐intrinsic and lasted up to adulthood. The pups nursed by mothers producing specific antibodies developed higher endogenous antibody titers of this specificity which perpetuated the effects of specific B cell selection into the mature follicular compartment, presumably by blocking auto‐Ag‐dependent development of transitional typeu20042 B cells in the spleen. This repertoire change was functional, as following infection of adult mice with VSV, those pups that had received specific maternal antibodies as neonates had increased pre‐immune titers and mounted strong early IgG neutralizing antibodies.

Combinatorial immunoglobulin light chain variability creates sufficient B cell diversity to mount protective antibody responses against pathogen infections

To analyze how combinatorial light (L) chain diversity influences the B cell repertoire, we studied mice with a homozygous immunoglobulin‐heavy‐chain null mutation (μMT), in which the B cell developmental block was overridden by the expression of a transgenic immunoglobulin μ heavy (H) chain derived from a vesicular stomatitis virus Indiana serotype (VSV‐IND)‐neutralizing Ab (T11μMT mice). The randomly integrated transgene could not undergo secondary rearrangements and was expressed in combination with endogenous κ or λ chains. T11μMT mice had a skewed B cell repertoire as evidenced by 30–60% VSV‐IND‐specific peripheral B cells and spontaneous VSV‐IND‐neutralizing serum titers. Upon immunization, T11μMT mice mounted specific IgM antibody responses against VSV‐IND but, interestingly, they also responded against VSV New Jersey serotype (VSV‐NJ), lymphocytic choriomeningitis virus, poliovirus and Salmonella typhi porins. Variable‐region sequence analysis revealed that VSV‐NJ‐specific antibodies expressed numerous L chains in combination with the transgenic H chain, which was devoid of hypermutations. Thus, in T11μMT mice combinatorial L chain variability alone is able to build up a sufficiently complex B cell repertoire to mount protective immunoglobulin responses against a variety of pathogens.