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

Eur J Immunol. 2005 May;35(5):1557-66. doi: 10.1002/eji.200425656.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation / immunology
  • Cytokines / immunology
  • Cytokines / metabolism
  • Dendritic Cells / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Granulocytes / immunology
  • Humans
  • Leukocytes, Mononuclear / immunology*
  • Membrane Glycoproteins / immunology*
  • Mice
  • Myeloid Differentiation Factor 88
  • Neutrophil Activation / immunology
  • Protamines / immunology*
  • Protamines / metabolism
  • RNA, Messenger / immunology*
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / immunology*
  • Receptors, Immunologic / immunology
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Toll-Like Receptors


  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Cytokines
  • MYD88 protein, human
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Protamines
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • TLR7 protein, human
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Toll-Like Receptors