Lymphotoxin-Mediated Crosstalk between B Cells and Splenic Stroma Promotes the Initial Type I Interferon Response to Cytomegalovirus

Schneider, Kirsten; Loewendorf, Andrea; Trez, Carl De; Fulton, J. D.; Rhode, Antje; Shumway, Heather; Ha, Sukwon; Patterson, Ginelle; Pfeffer, Klaus; Nedospasov, Sergei A.; Ware, Carl F.; Benedict, Chris A.

doi:10.1016/j.chom.2007.12.008

Cited by 124 publications

(174 citation statements)

References 61 publications

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“…Although the spleen and the liver are major sites of viral replication after this viral infection, YFP ϩ cells were only detectable in the spleen. However, IFN␤ mRNA expression levels are 1,000-fold lower in the liver, as compared with the spleen (31). In light of these findings and with the already low frequencies of YFP/IFN␤ ϩ cells (Ͻ0.1%) taken into account, the presence of potential IFN␤-producing cells in the liver cannot be excluded but might be below the detection level.…”

Section: Discussionmentioning

confidence: 66%

Visualization of IFNβ production by plasmacytoid versus conventional dendritic cells under specific stimulation conditions in vivo

Scheu

Dresing

Locksley

2008

Proc. Natl. Acad. Sci. U.S.A.

119

133

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Section: Discussionmentioning

confidence: 66%

Visualization of IFNβ production by plasmacytoid versus conventional dendritic cells under specific stimulation conditions in vivo

Scheu

Dresing

Locksley

2008

Proc. Natl. Acad. Sci. U.S.A.

119

133

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“…Previous studies have implicated the importance of both direct and indirect LTbR-mediated IFN-I induction in stromal cells and macrophages against CMV and vesicular stomatitis virus (21,49,50). Furthermore, the absence of LTbR signaling in mice results in a significant loss of IFN-I transcriptional signatures in the spleen in response to Listeria monocytogenes (51).…”

Section: Discussionmentioning

confidence: 99%

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

Maître

Cummings

et al. 2015

The Journal of Immunology

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Type I IFNs (IFN-I) are cytokines that can mediate both immune suppression and activation. Dendritic cells (DC) are significant producers of IFN-I, and depending on the context (nature of Ag, duration of exposure to Ag), DC-derived IFN-I can have varying effects on CD8+ T cell responses. In this study, we report that in the context of a CD8+ T cell response to a self-Ag, DC-intrinsic expression of IFN regulatory factor 3 is required to induce optimal proliferation and migration of autoreactive CD8+ T cells, ultimately determining their ability to infiltrate a target tissue (pancreas), and the development of glucose intolerance in rat insulin promoter–glycoprotein (RIP-GP) mice. Moreover, we show that signals through the lymphotoxin-β receptor (LTβR) in DC are also required for the proliferation of autoreactive CD8+ T cells, the upregulation of VLA4/LFA1 on activated CD8+ T cells, and their subsequent infiltration into the pancreas both in vitro and in vivo. Importantly, the defects in autoreactive CD8+ T cell proliferation, accumulation of CD8+ T cells in the pancreas, and consequent glucose intolerance observed in the context of priming by LTβR−/− DC could be rescued by exogenous addition of IFN-I. Collectively, our data demonstrate that the LTβR/IFN-I axis is essential for programming of CD8+ T cells to mediate immunopathology in a self-tissue. A further understanding of the IFN-I/LTβR axis will provide valuable therapeutic insights for treatment of CD8+ T cell–mediated autoimmune diseases.

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“…with the indicated doses of MCMV-Smith, obtained from the American Type Culture Collection (Manassas, VA). Stocks were derived from salivary glands of infected BALB/c mice as described elsewhere (14). The viral load in mice was determined by quantitative PCR as described previously (15), and data are normalized to results for ␤-actin.…”

Section: Cd70mentioning

confidence: 99%

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

Welten

Redeker

Toes

et al. 2016

J Virol

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Antibodies are implicated in long-term immunity against numerous pathogens, and because of this property, antibody induction is the basis for many vaccines. Little is known about the influence of viral persistence on the evolving antibody response. Here, we examined the characteristics of antibody responses to persistent infection by employing the prototypic betaherpesvirus family member cytomegalovirus (CMV) in experimental mouse models. During the course of infection, mouse CMV (MCMV)-specific IgM and IgG responses are elicited; however, IgG levels gradually inflate in the persistent phase of infection while IgM levels are stably maintained. Whereas CD27-CD70 interactions are dispensable, the CD28/B7 costimulatory pathway is critical for the class switching of MCMV-specific IgM-to-IgG B cell responses, which corresponds to the CD28/B7-dependent formation of CD4 ؉ T follicular helper cells (T FH ) and germinal center (GC) B cells. Furthermore, the initial viral inoculum dose dictates the height of the antibody levels during IgG antibody inflation and relates to the induction of long-lived plasma cells and memory B cells. Antibody avidity nonetheless is not altered after the establishment of viral persistence and occurs independently of the inoculum doses. However, repetitive challenge with intact viral particles, accompanied by increased GC reactivity, promotes the development of high-avidity IgG responses with neutralizing capacity. These insights can be used for the rational design of CMV-based vaccines aimed at inducing antibody responses. IMPORTANCE Antibodies provide long-term protection to different pathogens. However, how antibody responses develop during persistent virus infection is not entirely clear.Here, we characterize factors that influence the virus-specific antibody response to persistent CMV. This study describes that during persistent infection, CMV-specific IgM antibody levels are stably maintained while IgG2b and IgG2c levels gradually inflate over time. In contrast, the IgG avidity remains similar after the establishment of viral persistence. The induction of T follicular helper cells and GC B cells requires CD4 ؉ T cell help and CD28/B7 costimulation signals and is essential for the development of CMV-specific IgG antibody responses. Furthermore, neutralizing CMV-specific antibodies appear to develop late after infection, yet the neutralizing capacity can be improved upon repetitive viral challenge that is associated with increased GC reactivity. The results described here could inform the use of CMV-based vaccines and may help to understand how our immune system copes with this persistent virus.T he maintenance of long-lived humoral responses after infection and vaccination is attributed to both long-lived plasma cells that continuously produce antibodies and to memory B cells that are able to form antibody-secreting cells after reexposure (1, 2). Antibodies can protect against numerous pathogens by direct neutralization and/or by supporting effector functions of immune cells (1, ...

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Lymphotoxin-Mediated Crosstalk between B Cells and Splenic Stroma Promotes the Initial Type I Interferon Response to Cytomegalovirus

Cited by 124 publications

References 61 publications

Visualization of IFNβ production by plasmacytoid versus conventional dendritic cells under specific stimulation conditions in vivo

Visualization of IFNβ production by plasmacytoid versus conventional dendritic cells under specific stimulation conditions in vivo

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

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