The DC receptor DNGR-1 mediates cross-priming of CTLs during vaccinia virus infection in mice
Salvador Iborra, … , Caetano Reis e Sousa, David Sancho
Salvador Iborra, … , Caetano Reis e Sousa, David Sancho
Published April 16, 2012
Citation Information: J Clin Invest. 2012;122(5):1628-1643. https://doi.org/10.1172/JCI60660.
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Research Article

The DC receptor DNGR-1 mediates cross-priming of CTLs during vaccinia virus infection in mice

Abstract

In order to prime T cells, DCs integrate signals emanating directly from pathogens and from their noxious action on the host. DNGR-1 (CLEC9A) is a DC-restricted receptor that detects dead cells. Therefore, we investigated the possibility that DNGR-1 affects immunity to cytopathic viruses. DNGR-1 was essential for cross-presentation of dying vaccinia virus–infected (VACV-infected) cells to CD8+ T cells in vitro. Following injection of VACV or VACV-infected cells into mice, DNGR-1 detected the ligand in dying infected cells and mediated cross-priming of anti-VACV CD8+ T cells. Loss of DNGR-1 impaired the CD8+ cytotoxic response to VACV, especially against those virus strains that are most dependent on cross-presentation. The decrease in total anti-VACV CTL activity was associated with a profound increase in viral load and delayed resolution of the primary lesion. In addition, lack of DNGR-1 markedly diminished protection from infection induced by vaccination with the modified vaccinia Ankara (MVA) strain. DNGR-1 thus contributes to anti-VACV immunity, following both primary infection and vaccination. The non-redundant ability of DNGR-1 to regulate cross-presentation of viral antigens suggests that this form of regulation of antiviral immunity could be exploited for vaccination.

Authors

Salvador Iborra, Helena M. Izquierdo, María Martínez-López, Noelia Blanco-Menéndez, Caetano Reis e Sousa, David Sancho

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Figure 12

Inhibitors of lysosomal activity restore the cross-presentation ability of DNGR-1–deficient DCs.

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Inhibitors of lysosomal activity restore the cross-presentation ability ...
(A) Flt3L BMDCs from WT or Clec9agfp/gfp mice were left untreated or treated with bafilomycin A1 (Baf-A1) or leupeptin plus pepstatin (Leu/Pep). To analyze direct presentation or cross-presentation, the DCs were then cocultured for 2 hours with RAW-VACV (B) or RAW-VACV-UV (C) as in Figure 1. As a readout of the restimulation ability of the DCs, IFN-γ production was measured in polyclonal CD8+ T cells specific to VACV antigens, as in Figure 1. Production of IFN-γ is shown as mean ± SEM from a representative experiment (n = 3 biological replicates) of 3 experiments performed. Both Baf-A1 and Leu/Pep restore cross-presentation ability to Clec9agfp/gfp DCs. **P < 0.01, unpaired 2-tailed Student’s t test.