Early type I interferon‐mediated signals on B cells specifically enhance antiviral humoral responses

Fink, Katja; Lang, Karl S.; Manjarrez‐Orduño, Nataly; Junt, Tobias; Senn, Beatrice M.; Holdener, Martin; Akira, Shizuo; Zinkernagel, Rolf M.; Hengartner, Hans

doi:10.1002/eji.200635993

Cited by 108 publications

(110 citation statements)

References 44 publications

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“…In vivo evidence for a direct IFN-mediated role in B cell regulation has come from three recent studies. We provided evidence for direct IFN-mediated B cell stimulation to enhance virusspecific B cell responses to influenza virus infection (8), and similar findings were reported by Fink et al (28) The study presented here was conducted to more precisely define the nature of the innate signals that drive early local B cell activation during influenza infection and to determine the extent to which these stimuli modulate B cell responsiveness. Our data show that local secretion of type I IFN is the major innate signal stimulating respiratory tract B cells.…”

supporting

confidence: 85%

Influenza Virus Infection Causes Global Respiratory Tract B Cell Response Modulation via Innate Immune Signals

Chang¹,

Coro²,

Rau³

et al. 2007

The Journal of Immunology

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Induction of primary B cell responses requires the presence of Ag and costimulatory signals by T cells. Innate signals further enhance B cell activation. The precise nature and kinetics of such innate immune signals and their functional effects are unknown. This study demonstrates that influenza virus-induced type I IFN is the main innate stimulus affecting local B cells within 48 h of infection. It alters the transcriptional profile of B cells and selectively traps them in the regional lymph nodes, presumably via up-regulation of CD69. Somewhat paradoxically, innate B cell stimulation inhibited the ability of regional lymph node B cells to clonally expand following BCR-mediated stimulation. This inhibition was due to IFNR-signaling independent B cell intrinsic, as well as IFNR-dependent B cell extrinsic, regulation induced following influenza infection. IFNR-mediated signals also reduced B cell migration to various chemotactic agents. Consistent with the lack of responsiveness to CCR7 ligands, unaltered or reduced expression of MHC class II and genes associated with MHC class II Ag processing/presentation and CD40, B cells were unable to induce proliferation of naive CD4 T cells. Instead, they showed increased expression of a subset of nonclassical MHC molecules that facilitate interaction with γδ T cells and NK T cells. We conclude that type I IFN is the main “third” B cell signal following influenza infection causing early trapping of B cells in regional lymph nodes and, at a time when cognate T cell help is rare, enhancing their propensity to interact with innate immune cells for noncognate stimulation.

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supporting

confidence: 85%

Influenza Virus Infection Causes Global Respiratory Tract B Cell Response Modulation via Innate Immune Signals

Chang¹,

Coro²,

Rau³

et al. 2007

The Journal of Immunology

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“…Assuming the presence of Ͼ10 9 B cells in a mouse, basically all of which are IFNAR deficient (3, 10), Ͻ0.1% of the B cells can theoretically get infected upon injection of 2 ϫ 10 6 PFU VSV. Because, in absence of IFNAR, VSV-specific B cells do not seem to get preferentially infected (15), this would result in the infection and destruction of Ͻ0.1% of the VSV-specific B cell repertoire. Thus, the observations described in this work probably reflect the in vivo conditions more appropriately than adoptive transfer experiments.…”

Section: Discussionmentioning

confidence: 99%

“…In this model, IFNAR Ϫ/Ϫ mice, which showed a reduced frequency of influenza-specific B cells, produced a changed isotype pattern of influenza-specific Abs, and the differentiation of activated B cells to Ab-secreting plasma cells was hampered (14). Recent VSV infection studies conducted in mice carrying adoptively transferred transgenic VSV-specific B cells suggested that IFNAR signaling of B cells enhanced plasma blast formation and increased IgM responses (15). However, in these studies, the adoptively transferred IFNARdeficient B cells expressing a transgenic BCR competed with endogenous IFNAR-competent B cells.…”

mentioning

confidence: 99%

Vesicular Stomatitis Virus Glycoprotein Displaying Retrovirus-Like Particles Induce a Type I IFN Receptor-Dependent Switch to Neutralizing IgG Antibodies

Bach

Kamphuis

Odermatt

et al. 2007

The Journal of Immunology

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Vesicular stomatitis virus (VSV) infection rapidly induces IFN-αβ that confers initial survival, whereas long-term protection is mediated by neutralizing IgG responses. Because coadministration of IFN-αβ can enhance Ab responses against soluble Ags, we addressed whether virus-induced IFN-αβ also had an impact on the induction of neutralizing Ab responses. To this end, we generated apathogenic retrovirus-like particles (VLP) displaying the VSV gp (VLP-VSV). Reminiscent of live VSV, VLP-VSV induced VSV-neutralizing IgM responses that switched to IgG in a T help-dependent manner. In type I IFN receptor-deficient (IFNAR−/−) mice, VLP-VSV injection elicited neutralizing IgM, whereas the IgG switch was absent. The lack of subclass switch was associated with a reduced germinal center reaction. Conditional knockout mice with a lymphocyte-specific IFNAR ablation showed normal Ab responses against VLP-VSV, as well as against live VSV. Thus, IFNAR triggering critically promoted the T help-dependent subclass switch of virus-neutralizing Ab responses against VLP-VSV. Interestingly, in the context of VLP-VSV as well as VSV immunization, IFNAR triggering of B lymphocytes did not play a critical role.

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“…32 Gene expression analysis of collagen and 18S RNA was performed using kits from Applied Biosystems (Foster City, CA). For analysis, the expression levels of all target genes were normalized against 18S rRNA or GapDH mRNA (⌬Ct).…”

Section: Mrna Gene Profiling By Quantitative Rt-pcrmentioning

confidence: 99%

“…32 In brief, cells were stained for 15 minutes with tetramers at 37°C followed by incubation with the antibodies anti-CD8, anti-CD69, anti-CTLA4, anti-CD62L, or anti-CD44 (BD Bioscience, Franklin Lakes, NJ) or the antibodies anti-PD-1 or anti-IL-7R␣ (eBioscience, San Diego, CA). To measure intracellular IFN-␥ production, splenocytes were incubated with peptide for 6 hours at 37°C, for the last 5 hours with 1 mg/L Brefeldin A (Sigma-Aldrich, St Louis, MO), then stained for CD8 at 4°C.…”

Section: Fluorescence-activated Cell Sorting Analysismentioning

confidence: 99%

Hematopoietic cell–derived interferon controls viral replication and virus-induced disease

Lang

Cervantes-Barragán

Verschoor

et al. 2009

Blood

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Type I interferon (IFN-I) strongly inhibits viral replication and is a crucial factor in control- IntroductionInterferon is a polypeptide which has strong antiviral capacity. [1][2][3] Mice lacking the type I interferon (IFN-I) receptor are unable to limit widespread dissemination of several mouse pathogenic viruses, 4 which highlights the antiviral activity in vivo. Interferons are produced by a wide variety of cell types that are capable of responding to specific microbial elements (eg, double-and single-stranded RNA or DNA of viral origin) via pattern recognition receptors (PRRs). Some PRRs are widely expressed, whereas others are limited to specific cell populations. For instance, RIG-I, 5,6 TLR3, 7-9 and TLR9 10-13 induce IFN-I in a wide variety of hematopoietic and nonhematopoietic cell types as diverse as macrophages, fibroblasts, 14,15 endothelial cells, hepatocytes, 16-18 microglia, and even neurons. 19 In contrast, interferon-inducing Toll-like receptor 7 (TLR7) has only been reported on murine bone marrow (BM)-derived plasmacytoid dendritic cells. 20,21 Two main pathways have been characterized to induce IFN-I production: one through cytoplasmic PRRs, mainly the helicases RIG-I or MDA-5, 5 and the second through transmembrane PRRs, namely TLR3, TLR4, TLR7, and TLR9. [22][23][24][25] After virus recognition by the cytosolic PRRs or TLRs, Tank-binding kinase 1 (TBK1) is activated and induces phosphorylation of the transcription factors IRF3 and IRF7, which form homo-and heterodimers, and migrate into the nucleus. 26,27 IRF3 homodimers induce IFN-␤ production, but are not essential. In contrast, IRF7 (homo-and heterodimers with IRF3) is essential for the production of IFN-␣ via both cytosolic and transmembrane PRR pathways. 23 While irf3 Ϫ/Ϫ mice are still able to produce IFN-I, mice deficient in IRF7 are severely impaired in the production of IFN-I. Therefore, IRF7 has been assigned the master regulator of interferon. 28,29 Although many nonimmune cells possess the molecular elements that may allow them to produce IFN-I, the extent to which they participate in an effective IFN-I response during viral infection is not clear. In this report, we analyzed the contribution of hematopoietic versus nonhematopoietic cells in the production of IFN-I. As expression of IRF7 is essential for production of IFN-I, we used BM chimeras generated from irf7 Ϫ/Ϫ and wild-type (WT) mice. We found that during systemic viral infections, IFN-I from a BM-derived source was essential for the control of virus replication and inhibition of viral spread to peripheral organs. In addition, hematopoietic cell-derived IFN-I controlled disease onset and the extent of pathology. For personal use only. on April 11, 2019. by guest www.bloodjournal.org From cells at a multiplicity of infection (MOI) of 0.01 and plaqued on Vero cells. Lymphocytic choriomeningitis virus (LCMV) strain WE was originally obtained from F. Lehmann-Grube (Heinrich Pette Institute, Hamburg, Germany) and was propagated in L929 cells. Virus titers were measured usin...

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Early type I interferon‐mediated signals on B cells specifically enhance antiviral humoral responses

Cited by 108 publications

References 44 publications

Influenza Virus Infection Causes Global Respiratory Tract B Cell Response Modulation via Innate Immune Signals

Influenza Virus Infection Causes Global Respiratory Tract B Cell Response Modulation via Innate Immune Signals

Vesicular Stomatitis Virus Glycoprotein Displaying Retrovirus-Like Particles Induce a Type I IFN Receptor-Dependent Switch to Neutralizing IgG Antibodies

Hematopoietic cell–derived interferon controls viral replication and virus-induced disease

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