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

被引:164
作者
Scheel, B
Teufel, R
Probst, J
Carralot, JP
Geginat, J
Radsak, M
Jarrossay, D
Wagner, H
Jung, G
Rammensee, HG
Hoerr, I
Pascolo, S
机构
[1] CureVac GMBH, D-72076 Tubingen, Germany
[2] Inst Cell Biol, Dept Immunol, Tubingen, Germany
[3] Inst Res Biomed, Bellinzona, Switzerland
[4] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-8000 Munich, Germany
[5] Inst Organ Chem, Tubingen, Germany
关键词
RNA; protamine; B cell; DC; TLR;
D O I
10.1002/eji.200425656
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-alpha and IFN-alpha 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.
引用
收藏
页码:1557 / 1566
页数:10
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