Presentation of exogenous antigen in the context of MHC class I molecules — cross-presentation — can result in CD8+ T-cell priming (cross-priming) or CD8+ T-cell tolerance (cross-tolerance). New insight into the signals that determine which of these fates is adopted by the CD8+ T cell is provided by a report in Nature, which indicates that stimulation of Toll-like receptor 3 (TLR3) promotes cross-priming.

CD8α+ dendritic cells (DCs) are crucial components of the antiviral response in mice, priming virus-specific cytotoxic T lymphocytes (CTLs). They are also the principal mediator of cross-presentation in vivo. So, Schulz et al. proposed that CD8α+ DCs that are cross-presenting antigens from phagocytosed virally infected cells must receive a signal to favour cross-priming. Given that viral infection is associated with the generation of double-stranded RNA (dsRNA) and that CD8α+ DCs express the dsRNA receptor TLR3, they set out to investigate whether TLR3 might provide this signal.

CD8α+ DCs cultured in the presence of Vero cells (a primate cell line) that had been loaded with synthetic dsRNA (polyinosinic–polycytidylic acid, polyI:C) and exposed to ultraviolet light to induce cell death phagocytosed the polyI:C-loaded Vero cells. This induced increased cell-surface expression of CD40, CD80 and CD86, and increased production of inflammatory cytokines, including interleukin-6. By contrast, mock-treated cells did not induce activation of the CD8α+ DCs. Similar uptake and activation was observed when CD8α+ DCs were cultured in the presence of Vero cells infected with either encephalomyocarditis virus or Semliki Forest virus (SFV). Phagocytosis and phagosomal acidification were essential for the polyI:C-loaded Vero cells to induce CD8α+ DC activation, and further studies showed that TLR3 was also required for activation induced by either infected or polyI:C-loaded Vero cells.

Mice were immunized either with Vero cells infected with SFV that had been genetically modified to produce no progeny and to express ovalbumin (OVA) or with Vero cells loaded with OVA in the presence or absence of polyI:C. Efficient cross-priming of OVA-specific CTLs was observed only in those mice immunized with the virally infected cells or with the Vero cells loaded with OVA in the presence of polyI:C. Further evidence that an intrinsic TLR3 signal induces cross-priming by CD8α+ DCs was provided by the observation that neither TLR3-deficient mice nor lethally irradiated wild-type mice reconstituted with TLR3-deficient bone marrow could cross-prime CTLs after immunization with the virally infected cells or with the Vero cells loaded with OVA in the presence of polyI:C.

This study indicates that TLR3 expression by CD8α+ DCs functions to sense viruses that do not infect DCs and to induce the cross-presentation of cell-associated viral antigens such that CD8+ T-cell cross-priming occurs. TLR3 ligation is unlikely to provide the only signal that elicits cross-priming, and the authors suggest that virally induced type I interferons might function synergistically with TLR3-initiated signals to promote cross-priming.