Abstracts (complete list) - Wissenschaft Online

Frank Schmitz, Antje Heit, Tobias Haas, Hermann Wagner
An mTOR dependent transport mechanism of cytosolic
receptors licenses TLR-independent recognition of nucleic
acids
Nucleic acid recognition by innate receptors constitutes an integral part of the
mammalian anti-viral immune responses. The endosomally expressed Toll-like receptors
(TLR)-3 and -9 recognize natural and synthetic double stranded (ds)RNA and single
stranded (ss)DNA, respectively. The synthetic mimics of dsRNA, Poly I:C, and ssDNA
(CpG-ODN) have been reported to display synergistic activation of innate immune cells
and subsequent enhanced production of type I interferons, ultimative leading to
increased cytotoxic T cell responses.
When stimulating myeloid dendritic cells (mDC) with those ligands, we made the
unexpected observation, that the production of interferon alpha (IFNa), so far
considered a key feature of plasmacytoid DCs, is independent of TLR-3 and -9. The
restricted translocation of both ligands to endosomal/lysosomal compartments leads us
to hypothesize that the non-TLR nucleic acid receptors RIG-I and Mda5 are involved. To
date, these receptors are described to operate exclusively in the cytosol. To elucidate
the mechanism allowing cytosolic receptors to respond to endosomally located ligands,
we investigated the role of autophagy, a process for transport of cytosolic material to
lysosomes. Indeed, chemical inhibitors of autophagy did significantly reduce the
observed IFNa production. Further, rapamycin, and inductor of autophagy operating at
the cellular kinase mTOR was capable to increase the cellular response both to CpG-
ODN plus Poly I:C and to Poly I:C alone.
These findings suggest a novel transport mechanism of cytosolic receptors to
endosomes/lysosomes for the recognition of extracellular nucleic acids. Ultimatively,
this process may mechanistically explain the immunogeneicity of apoptotic host-cells to
induce tumor-protective T cell responses.