Interferon-α and Interleukin-12 Are Induced Differentially by Toll-like Receptor 7 Ligands in Human Blood Dendritic Cell Subsets

Ito, Tomoki; Amakawa, Ryuichi; Kaisho, Tsuneyasu; Hemmi, Hiroaki; Tajima, Kenichirou; Uehira, Kazutaka; Ozaki, Yoshio; Tomizawa, Hideyuki; Akira, Shizuo; Fukuhara, Shirou

doi:10.1084/jem.20020207

Cited by 413 publications

(375 citation statements)

References 29 publications

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“…The cellular pattern of immunostimulation by protamine-RNA complexes indicates that TLR-1, TLR-7, or TLR-8 may be the receptors for protamine-RNA. These three receptors are the only known receptors of the IL-1 receptor family expressed on pDC, mDC, granulocytes, monocytes and NK cells [21][22][23][24][25]. At the same time, mRNA coding for TLR-1, -7 and -8 are detectable in purified human T cells [21].…”

Section: Discussionmentioning

confidence: 99%

Toll‐like receptor‐dependent activation of several human blood cell types by protamine‐condensed mRNA

Scheel

Teufel

Probst³

et al. 2005

Eur J Immunol

177

154

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We reported that RNA condensed on protamine is protected from RNase-mediated degradation and can be used for vaccination. Here, we show that such complexes are also danger signals that activate mouse cells through a MyD88-dependent pathway. Moreover, mRNA-protamine complexes stimulate human blood cells. They strongly activate DC and monocytes, leading to TNF-a and IFN-a secretion. In addition, protamine-RNA complexes directly activate B cells, NK cells and granulocytes. The detailed analysis of the activated cell types, the study of the cytokines released from PBMC cultured with protamine-RNA complexes and recently published results suggest that TLR-7 and TLR-8 may be involved in the recognition of protamine-stabilized RNA. Our data indicate that protamine-stabilized RNA, which may be similar to RNA condensed in the nucleocapsids of RNA viruses, is a strong danger signal. Thus, similarly to plasmid DNA, protamine-RNA combines antigen production and non-specific immunostimulation. The studies presented here explain the capacity of protamine-RNA to act as a vaccine, and pave the way towards the development of safe and efficient mRNA-based immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Toll‐like receptor‐dependent activation of several human blood cell types by protamine‐condensed mRNA

Scheel

Teufel

Probst³

et al. 2005

Eur J Immunol

177

154

View full text Add to dashboard Cite

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“…However, TLR-3 does not appear to be expressed on such cells (64). TLR-7 mediates induction of IFN␣ by imidazoquinoline compounds (68), but the natural ligand(s) is unknown. TLR-7 and TLR-9, both capable of activating production of IFN␣, should therefore be investigated for the ability to recognize RNA present in IICs.…”

Section: Discussionmentioning

confidence: 99%

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

Lövgren

Eloranta

Båve

et al. 2004

Arthritis & Rheumatism

498

409

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Objective. To investigate the release of interferon-␣ (IFN␣)-inducing material by necrotic or apoptotic cells, its properties, and the necessity of autoantibodies from systemic lupus erythematosus (SLE) patients for the interferogenic activity.Methods. U937 monocytic leukemia cells or peripheral blood mononuclear cells (PBMCs) were rendered necrotic by freeze-thawing or apoptotic by treatment with ultraviolet light. Cell culture supernatants from these cells and IgG from SLE patients (SLE IgG) were added to cultures of normal PBMCs or purified plasmacytoid dendritic cells (PDCs). The importance of nucleic acids for IFN␣ induction was investigated by RNase and DNase treatment. The IFN␣ levels were measured by immunoassay.Results. Both necrotic and apoptotic U937 cells released material that, combined with SLE IgG, induced IFN␣ production in PDCs. The release from apoptotic cells occurred with a 16-hour delay, in late apoptosis. Also, normal PBMCs released IFN␣-inducing material, but only during necrosis. The interferogenic activity of the necrotic material required the presence of RNA, while both RNA and DNA were important in the apoptotic material. In both cases, the presence of SLE IgG was necessary, and its activity correlated with the presence of antibodies to RNA-binding proteins, but not anti-DNA antibodies.Conclusion. Necrotic and late apoptotic cells release material that, combined with SLE IgG, induces production of IFN␣ in PDCs. The IFN␣ inducers probably consist of immune complexes (ICs) containing RNA and possibly DNA as essential interferogenic components. The presence of such interferogenic ICs could explain the ongoing production of IFN␣ in SLE and could be of etiopathogenic importance.

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“…The dependence of mammalian immunity on T-and B-cell function and, in turn, the dependence of these cell types on RAG-mediated somatic recombination and subsequent diversification of antigen-receptor genes has understandably resulted in a focus on lymphocytes as the central components of mammalian immunity. However, increasing attention has recently been paid to the interactions of T and B cells with innate immune effectors, and this has produced important insights regarding functional bridges between innate and adaptive immune cells during infection [11][12][13][14][15][16]139,140 . An increasingly rich picture of the diversity of innate immune surveillance and recognition in vertebrates is developing.…”

Section: Discussionmentioning

confidence: 99%

Reconstructing immune phylogeny: new perspectives

2005

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Numerous studies of the mammalian immune system have begun to uncover profound interrelationships, as well as fundamental differences, between the adaptive and innate systems of immune recognition. Coincident with these investigations, the increasing experimental accessibility of non-mammalian jawed vertebrates, jawless vertebrates, protochordates and invertebrates has provided intriguing new information regarding the likely patterns of emergence of immune-related molecules during metazoan phylogeny, as well as the evolution of alternative mechanisms for receptor diversification. Such findings blur traditional distinctions between adaptive and innate immunity and emphasize that, throughout evolution, the immune system has used a remarkably extensive variety of solutions to meet fundamentally similar requirements for host protection.The evolutionary development of the METAZOANS was associated with the diversification of a wide range of specialized cell-surface molecules that mediate key metabolic processes, as well as provide crucial contact interfaces and carry out a broad range of other essential functions. It is not unexpected that some of these molecules also came to function as barriers to pathogenic invasion and, in doing so, began to carry out dedicated innate immune protective functions. Whereas the simplest form of protection, barrier formation, is essentially mechanical in nature, relentless pressure from genetic variation in pathogens probably drove the evolution of such innate immune protective molecules towards diversification and, in parallel, towards integration of signalling pathways to regulate cellular responses to external stimulation. However, despite the sophistication that such innate immune mediators achieved over time, their biological complexity, by definition, would be limited by genome space, so with increasing complexity of body plan and/or increasing pathogen sophistication, they could be overwhelmed. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMore than 500 million years ago, a TRANSPOSITION event, probably involving a recombinationactivating gene (RAG)-bearing element, might have given rise to the predecessors of the rearranging antigen-binding receptors of the jawed vertebrates, which encompass the vertebrate radiations that extend from the cartilaginous fish through to humans. This is considered the defining point in the emergence of RAG-mediated (conventional) adaptive immunity 1,2 , which has evolved to create a mechanism for deriving almost limitless variation from very few genes. Studies in traditional and non-traditional animal models, such as sharks, bony fish and birds, have brought this event and its ramifications for host defence into sharper focus. We can now predict much about how these rearranging antigenbinding receptors probably arose, what alternative pathways of immune-receptor gene evolution have occurred, what relationships exist between B-and T-cell-mediated immunity and natural killer (NK)-cell function, how complex immune ...

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Interferon-α and Interleukin-12 Are Induced Differentially by Toll-like Receptor 7 Ligands in Human Blood Dendritic Cell Subsets

Cited by 413 publications

References 29 publications

Toll‐like receptor‐dependent activation of several human blood cell types by protamine‐condensed mRNA

Toll‐like receptor‐dependent activation of several human blood cell types by protamine‐condensed mRNA

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

Reconstructing immune phylogeny: new perspectives

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