Cutting Edge: IL-21 and TLR Signaling Regulate Germinal Center Responses in a B Cell-Intrinsic Manner

Bessa, Juliana; Köpf, Manfred; Bachmann, Martin F.

doi:10.4049/jimmunol.0903949

Cited by 109 publications

(132 citation statements)

References 27 publications

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“…In contrast with TFH cell development, we found that day 7 GC formation and early Ab production to the T-dependent Ag NP-CGG were dependent on IL-21R. These observations are similar to initial studies reported by Ozaki et al (14) as well as others published while this manuscript was under review (17)(18)(19)(20). A time-course analysis performed following primary immunization revealed that the absolute number of Agspecific GC B cells was similar in WT and IL-21R.KO mice from day 14-28.…”

Section: Discussionsupporting

confidence: 70%

“…CD4 + TFH cells play a critical role in promoting GC-dependent Ab responses, and IL-21 can impact the development and/or maintenance of TFH cells (15, 16, 20, 38). However, this requirement is not absolute and appears sensitive to the time-point(s) examined and immunogen used (17)(18)(19). In our studies, we found that the generation and maintenance of TFH cell numbers was similar in IL-21R.KO and WT mice following immunization with NP-CGG, indicating that IL-21R was not required for these processes during the time points examined.…”

Section: Discussionsupporting

confidence: 50%

“…Following immunization with TD Ags, IL-21R.KO mice have reduced Ag-specific IgG1 Ab titers and TFH cell numbers on days 7-10 of the primary immune response (14)(15)(16). Recent studies have shown that IL-21 plays an important role in the formation of GCs following immunization with T dependent Ags (17)(18)(19)(20). In vitro, stimulation with IL-21 and anti-CD40 can induce the differentiation of naive and memory B cells into isotype-switched B cells (21)(22)(23).…”

Section: T He Development Of Ab Responses Occurs In Distinct Stagesmentioning

confidence: 99%

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IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

Rankin

MacLeod

Keegan

et al. 2011

The Journal of Immunology

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Development of long-term humoral immunity, characterized by the formation of long-lived plasma cells (PCs) in the bone marrow and memory B cells, is a critical component of protective immunity to pathogens, and as such it is the major goal of vaccination. However, the mechanisms involved in the generation of long-term humoral immunity remain poorly understood. In this study, we used IL-21R–deficient (IL-21R.KO) mice to examine the role of the IL-21 pathway in the development of the B cell memory response. Primary IgG serum Ab responses to the T cell-dependent Ag 4-hydroxy-3-nitrophenylacetyl (NP) hapten conjugated to chicken γ globulin were delayed in IL-21R.KO mice, but reached normal titers within 3 to 4 wk of immunization. IL-21R.KO mice formed germinal centers and generated normal numbers of PCs in their bone marrow. Additionally, memory B cell formation was similar in wild-type and IL-21R.KO mice. However, NP-specific memory B cells and PCs failed to expand following secondary immunization of IL-21R.KO mice, and consequently, secondary IgG Ab responses to NP hapten conjugated to chicken γ globulin were significantly impaired. These results identify the IL-21 pathway as a critical component of the memory B cell response.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionsupporting

confidence: 50%

Section: T He Development Of Ab Responses Occurs In Distinct Stagesmentioning

confidence: 99%

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IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

Rankin

MacLeod

Keegan

et al. 2011

The Journal of Immunology

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“…Tfh cells are a subset of activated CD4 1 T cells and are specialized to regulate B-cell-mediated humoral immunity [11,27]. Furthermore, a recent study suggested that persistent infection of virus could drive the differentiation of helper T cells to Tfh cells [28].…”

Section: Discussionmentioning

confidence: 99%

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

Yang

et al. 2011

Eur J Immunol

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The role of TLR signaling in linking the innate and adaptive immune systems has been a controversial issue that remains to be solved. Here, we determined whether MyD88-dependent TLR signals are required for the generation of B-cell responses during chronic Salmonella infection. Oral administration of recombinant attenuated Salmonella enterica serovar Typhimurium vaccine (RASV) strain in MyD88 À/À mice resulted in chronic infection. Infection was accompanied by enlarged germinal centers and hypergammaglobulinemia with anti-double-stranded DNA (dsDNA)-specific Ab in sera, and the deposition of immune complexes in the kidneys, suggesting onset of autoimmunity. CD4 1 T cells expressing PD-1, CXCR5, ICOS, and IL-21 were dramatically increased in chronically infected mice, indicating the expansion of follicular helper T (Tfh)-like cells. Of note, the depletion of CD4 1 T cells completely blocked the generation of polyclonal IgG Ab in sera after oral RASV challenge. Inflammatory myeloid cells expressing CD11b and Gr-1 accumulated in high numbers in the spleen of MyD88 À/À mice. Interestingly, the blockade of PD-1 or ICOS significantly reduced the hypergammaglobulinemia and dsDNA-specific autoantibody production. Overall, these results suggest that Tfh-like cells in chronic bacterial infection trigger autoimmune hypergammaglobulinemia in a PD-1-and ICOSdependent manner.

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“…It is important to note that upon assembly of the M2e-AP205 coat protein fusion protein, Escherichia coli RNA is packaged into the VLPs. We have previously shown for VLPs from RNA-phages that removal of the RNA results in a shift of the IgG isotypes induced from IgG2a/c to IgG1 [32][33][34], whereas IgG3 was only marginally affected [33]. Furthermore, presence of RNA also promoted the induction of IgG2b antibodies, which was, however, the subdominant subclass compared with IgG2a/c.…”

mentioning

confidence: 87%

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

Schmitz¹,

Beerli²,

Bauer³

et al. 2012

Eur J Immunol

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A vaccine protecting against all influenza strains is a long-sought goal, particularly for emerging pandemics. As previously shown, vaccines based on the highly conserved extracellular domain of M2 (M2e) may protect against all influenza A strains. Here, we demonstrate that M2e-specific monoclonal antibodies (mAbs) protect mice from a lethal influenza infection. To be protective, antibodies had to be able to bind to Fc receptors and fix complement. Furthermore, mAbs of IgG2c isotype were protective in mice, while antibodies of identical specificity, but of the IgG1 isotype, failed to prevent disease. These findings readily translated into vaccine design. A vaccine targeting M2 in the absence of a toll-like receptor (TLR) 7 ligand primarily induced IgG1, whilst the same vaccine linked to a TLR7 ligand yielded high levels of IgG2c antibodies. Although both vaccines protected mice from a lethal challenge, mice treated with the vaccine containing a TLR7 ligand showed significantly lower morbidity. In accordance with these findings, vaccination of TLR7 -/-mice with a vaccine containing a TLR7 ligand did not result in protection from a lethal challenge. Hence, the innate immune system is required to direct isotype switching toward the more protective IgG2a/c antibodies.Keywords: Antibodies r Immunotherapy r Toll like receptors r Vaccination r Virology IntroductionInfection with influenza virus is a major cause of morbidity as well as mortality throughout the world. Influenza virus is a very dynamic pseudo species and constantly avoids immunity at the population level by accumulating mutations in the hemagglutinin (HA) and neuraminidase molecules in a process called genetic drift. In addition, in a rare process called genetic shift, human influenza viruses may reassort with avian or swine influenza viruses [1]. Since under these circumstances, the virus hits an essentially naive population, the epidemic may become a pandemic with potentially millions of people infected and killed by the virus.Correspondence: Dr. Martin F. Bachmann e-mail: martin.bachmann@me.com Induction of protective immunity against influenza virus, not affected by genetic drift or shift, is therefore a major goal in vaccine development [2,3]. T cells are usually more cross-reactive than antibodies [4][5][6] and additionally recognize more conserved, virus-internal proteins [7,8]. Induction of broadly reactive T cells by vaccination may therefore be a potential avenue to follow [9,10]. This, however, may be a difficult task, since protective T-cell responses are usually short lived in mice [11] and humans [12], and it has not been possible so far to induce long-lived T-cell mediated immunity by vaccination. An alternative approach represents the induction of protective antibody responses directed against conserved viral structures. The extracellular domain of M2 (M2e) is a candidate for such a vaccine. M2e is highly conserved in all influenza A strains and has hardly changed over the last 90 years [13,14]. Although the recently emerged pandemic influ...

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Cutting Edge: IL-21 and TLR Signaling Regulate Germinal Center Responses in a B Cell-Intrinsic Manner

Cited by 109 publications

References 27 publications

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

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