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 7

The CD8+ T cell effector response to vaccinia epitopes is decreased in the absence of DNGR-1.

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The CD8+ T cell effector response to vaccinia epitopes is decreased in t...
(A–C) Absence of DNGR-1 impairs the CD8+ T cell effector response to early and late vaccinia peptides. (A) WT or DNGR-1–deficient mice were infected i.d. in the ear with WR (B) or ΔB13R (C) VACV strains, and 7 days later, ear dermal cell suspensions were obtained and restimulated with B8R and A3L VACV peptides. Upper panels show representative dot plot sets. Lower panels show individual data for production of IFN-γ from a representative experiment (n = 4 biological replicates) of 3 performed. (D–F) CTL killing activity in vivo against vaccinia epitopes is reduced in DNGR-1–deficient mice. (D) WT or DNGR-1–deficient mice were infected with WR (E) or ΔB13R (F) VACV i.d. in the ear, and killing assays were conducted on day 6 as in Figure 4. Upper panels show representative histogram sets. Control histograms from non-infected mice to show the proportion of transferred targets. Lower panels show the percentage specific killing in a representative experiment of 3 performed is shown. Data are presented as mean ± SEM (n = 4 biological replicates). *P < 0.05, **P < 0.01, unpaired 2-tailed Student’s t test.