Toll-like receptor 7–induced naive human B-cell differentiation and immunoglobulin production

Glaum, Mark C.; Narula, Shilpi; Song, Decheng; Zheng, Yi; Anderson, A.; Pletcher, Charles H.; Levinson, Arnold I.

doi:10.1016/j.jaci.2008.09.018

Cited by 46 publications

(43 citation statements)

References 35 publications

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“…Several recent in vitro studies, however, have found that TLR ligands can directly induce Ab secretion from both naive and memory B cells (29) and induce their differentiation into plasma cells (30) in the absence of T cell help. Conjugation of Ag to TLR ligands also appears to be beneficial for Ab responses where simultaneous triggering of B cell receptor together with TLR engagement can lead to enhanced Ag-specific B cell responses (31).…”

Section: Discussionmentioning

confidence: 98%

Soluble Proteins Induce Strong CD8+ T Cell and Antibody Responses through Electrostatic Association with Simple Cationic or Anionic Lipopeptides That Target TLR2

Chua

Pejoski

Turner

et al. 2011

The Journal of Immunology

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The low immunogenicity exhibited by most soluble proteins is generally due to the absence of molecular signatures that are recognized by the immune system as dangerous. In this study, we show that electrostatic binding of synthetic branched cationic or anionic lipopeptides that contain the TLR-2 agonist Pam2Cys markedly enhance a protein’s immunogenicity. Binding of a charged lipopeptide to oppositely charged protein Ags resulted in the formation of stable complexes and occurs at physiologic pH and salt concentrations. The induction of cell-mediated responses is dependent on the electrostatic binding of lipopeptide to the protein, with no CD8+ T cells being elicited when protein and lipopeptide possessed the same electrical charge. The CD8+ T cells elicited after vaccination with lipopeptide–protein Ag complexes produced proinflammatory cytokines, exhibited in vivo lytic activity, and protected mice from challenge with an infectious chimeric influenza virus containing a single OVA epitope as part of the influenza neuraminidase protein. Induction of a CD8+ T cell response correlated with the ability of lipopeptide to facilitate Ag uptake by DCs followed by trafficking of Ag-bearing cells into draining lymph nodes. Oppositely charged but not similarly charged lipopeptides were more effective in DC uptake and trafficking. Very high protein-specific Ab titers were also achieved by vaccination with complexes composed of oppositely charged lipopeptide and protein, whereas vaccination with similarly charged constituents resulted in significant but lower Ab titers. Regardless of whether similarly or oppositely charged lipopeptides were used in the induction of Ab, vaccination generated dominant IgG1 isotype Abs rather than IgG2a.

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Section: Discussionmentioning

confidence: 98%

Soluble Proteins Induce Strong CD8+ T Cell and Antibody Responses through Electrostatic Association with Simple Cationic or Anionic Lipopeptides That Target TLR2

Chua

Pejoski

Turner

et al. 2011

The Journal of Immunology

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“…Kang and colleagues showed that MyD88 Ϫ/Ϫ mice produced lower levels of circulating IgM and fewer IgM ϩ ASCs in the spleen and BM following influenza virus-like particle vaccination (28). The association between TLR7 signaling and IgM production is also apparent in human B-cell responses (5,19,21). The precise long-term consequence of reduced IgM production as a result of TLR7 deficiency remains unclear.…”

Section: Fig 3 Tlr7mentioning

confidence: 99%

TLR7 Recognition Is Dispensable for Influenza Virus A Infection but Important for the Induction of Hemagglutinin-Specific Antibodies in Response to the 2009 Pandemic Split Vaccine in Mice

Jeisy-Scott

Kim

Davis

et al. 2012

J Virol

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Recognition of pathogen-associated molecular patterns by pattern recognition receptors of the innate immune system is crucial for the initiation of innate and adaptive responses and for immunological memory. We investigated the role of TLR7 in the induction of adaptive immunity and long-term memory following influenza virus infection and vaccination in C57BL/6 mice. During infection with influenza A/PR8/34 virus, the absence of either TLR7 or MyD88 leads to reduced virus-specific antibodies in the serum and antibody-secreting cells in their secondary lymphoid organs, particularly in bone marrow. In spite of this, the absence of TLR7/MyD88 signaling did not impair the production of protective antibodies. Following immunization with the 2009 pandemic inactivated split vaccine, TLR7 −/− mice had significantly lower levels of germinal center formation, antibody-secreting cells, and circulating influenza virus-specific antibodies than control animals. Consequently, TLR7 −/− mice failed to develop protective immunological memory upon challenge. Furthermore, the immunogenicity of the split vaccine was likely due to TLR7 recognition of virion RNA, as its removal from the split vaccine significantly reduced the levels of influenza virus-specific antibodies and compromised the vaccine protective efficacy in mice. Taken together, our data demonstrate that TLR7 plays an important role in vaccine-induced humoral immune responses to influenza virus through the interaction with viral RNA present in the split vaccine.

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“…This confirms previous reports demonstrating that activation of naive B cells in the presence of TLR7 or TLR9 agonists induces differentiation into ASCs. 26,27 Importantly, we only observed differentiation of naive B cells into IgMproducing ASCs in the presence of both CD4 ϩ T cells and TLR7 or a mixture of TLR7 and TLR9 agonists.…”

Section: Discussionmentioning

confidence: 90%

T cell–independent restimulation of FVIII-specific murine memory B cells is facilitated by dendritic cells together with toll-like receptor 7 agonist

Pordes

Baumgartner²,

Allacher

et al. 2011

Blood

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Memory B cells are involved in long-term maintenance of antibody-dependent immunologic disorders. Therefore, it is essential to understand how the restimulation of FVIII-specific memory B cells in hemophilia A with FVIII inhibitors is regulated. We asked whether concurrent activation of the innate immune system by an agonist for toll-like receptor (TLR) 7 is able to facilitate the differentiation of FVIIIspecific memory B cells in the absence of T-cell help. TLR7 recognizes singlestranded RNA as contained in RNA viruses such as influenza, Sendai, and Coxsackie B viruses. Our results indicate that highly purified murine memory B cells do not differentiate into FVIII-specific antibody-secreting cells in the presence of FVIII and the TLR7 agonist when cultured in the absence of CD4 ؉ T cells. However, CD11c ؉ dendritic cells facilitate the T cell-independent differentiation of FVIII-specific memory B cells but only in the presence of FVIII and the TLR7 agonist. In contrast to T cell-dependent restimulation, the antibody response after T cell-independent restimulation of FVIIIspecific memory B cells is skewed toward IgG2a, an antibody subclass that is efficient in activating the complement system and in inducing Fc-receptormediated effector functions, both are required for effective immune responses against pathogens. (Blood. 2011;118(11): 3154-3162) IntroductionMemory B cells are essential to maintain antibody-dependent immunologic memory that is required for long-lasting protection against invading pathogens such as viruses and bacteria. After encounter with their specific antigen, memory B cells can rapidly proliferate and differentiate into antibody-secreting plasma cells (ASCs), thereby replenishing the pool of plasma cells. 1 Moreover, memory B cells act as efficient antigen-presenting cells for the restimulation of CD4 ϩ T cells because they express high-affinity antigen receptors, major histocompatibility complex class II molecules, and costimulatory molecules. 2 However, memory B cells are also involved in long-term maintenance of immunopathologic conditions such as chronic antibody-dependent immunologic disorders, 3 which would indicate that memory B cells have to be eradicated for successful treatment of such diseases.We and others have demonstrated the presence of FVIII-specific memory B cells in the circulation of patients with FVIII inhibitors. [4][5][6] Furthermore, several studies have suggested that FVIIIspecific memory B cells are down-regulated during successful immune tolerance induction therapy in patients with hemophilia A and FVIII inhibitors. 5,6 These results indicate that FVIII-specific memory B cells might be essential for maintaining immunologic memory for antibodies against FVIII in patients. Therefore, it is important to understand the regulation of FVIII-specific memory B cells and to find new approaches to specifically eradicate these cells.We used a murine model of hemophilia A to study the regulation of FVIII-specific memory B cells in vitro. We demonstrated previously that the rest...

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Toll-like receptor 7–induced naive human B-cell differentiation and immunoglobulin production

Cited by 46 publications

References 35 publications

Soluble Proteins Induce Strong CD8+ T Cell and Antibody Responses through Electrostatic Association with Simple Cationic or Anionic Lipopeptides That Target TLR2

Soluble Proteins Induce Strong CD8+ T Cell and Antibody Responses through Electrostatic Association with Simple Cationic or Anionic Lipopeptides That Target TLR2

TLR7 Recognition Is Dispensable for Influenza Virus A Infection but Important for the Induction of Hemagglutinin-Specific Antibodies in Response to the 2009 Pandemic Split Vaccine in Mice

T cell–independent restimulation of FVIII-specific murine memory B cells is facilitated by dendritic cells together with toll-like receptor 7 agonist

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