Immunology: Toll-like receptor 3 signaling enables cross-priming

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Dendritic cells use Toll-like receptor 3 to promote cross-priming of cytotoxic T cells (CTLs) against virally infected cells.

Cross-presentation allows antigen presenting cells (APCs) to prime T cells with antigens that are not expressed by the APCs themselves, but acquired by the phagocytosis of dying cells. Schulz et al. now show that for dendritic cells (DCs) — the most important type of APC — activation of Toll-like receptor 3 (TLR3) with viral double-stranded RNA (dsRNA) is a pre-requisite for an efficient in vivo T cell response against virus-infected cells during cross-presentation.

Cross-presentation can result either in CD8⁺ T cell inactivation (tolerance), or a cytotoxic T cell (CTL) response (cross-priming). Cross-presentation of virus-infected cells frequently leads to cross-priming and signals associated with viral infection are thought to tilt the balance to a CTL response.

While trying to identify these signals, Schulz et al. found high TLR3 expression in phagocytosing CD8 alpha ⁺ DCs. As it is known that viral dsRNA binding to TLR3 leads to DC activation, the authors hypothesized that TLR3 may be responsible for sensing the presence of a viral infection in phagocytosed cellular material and that this may play an important role in cross-priming.

To test this, the authors showed that synthetic dsRNA transfected into a number of cell lines or virus-infected cells can activate CD8 alpha ⁺ DCs after they have been phagocytosed. No activation could be seen when phagocytosis was blocked by actin-stabilizing agents, suggesting that phagocytosis and phagosomal acidification — but not soluble factors — are necessary for activation. Since in Tlr3 ^-/- CD8 alpha ⁺ DCs no such activation was seen, these findings suggest that TLR3-dependent recognition of dsRNA in phagosomes mediates the activation of CD8 alpha ⁺ DCs.

To investigate virus- and dsRNA-induced cross-priming of T cells in vivo, Schulz et al. immunized mice with Vero cells transfected with dsRNA and ovalbumin (OVA), or with cells infected with a replication-deficient virus encoding OVA. While wild-type mice exhibited robust cross-priming, TLR3-deficient mice were strongly impaired for cross-priming. The authors repeated the experiments with lethally irradiated animals that were reconstituted with bone marrow from Tlr3 ^-/- or Tlr3 ^+/+ donors and with OVA-specific T cells. The increase in conferred cell immunogenicity was completely lost in the Tlr3 ^-/- chimeras, showing the dependency of cross-priming on TLR3 expressing APCs.

Thus, the work by Schulz et al. has identified TLR3 as a key factor for cross-priming of CTLs against viruses that do not directly infect dendritic cells. As TLR3 signaling also leads to upregulation of co-stimulatory molecules, the production of immunomodulatory cytokines and IFN- alpha / beta induction, loading tumor cells with dsRNA could constitute potent vaccines for cancer therapy.

Markus Wagner
Nature Cell Biology

References

Schulz, Oliver, Diebold, Sandra S., Chen, Margaret, Näslund, Tanja I., Nolte, Martijn A., Alexopoulou, Lena, Azuma, Yasu-Taka, Flavell, Richard A., Liljeström, Peter, & Sousa, Caetano Reis E. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433, 887–892 (24 February 2005); nature03326 | Article | PubMed |