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 11

Syk deficiency in CD11c+ cells impairs the CD8+ T cell effector response to VACV infection.

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Syk deficiency in CD11c+ cells impairs the CD8+ T cell effector response...
(A–C) CD11c-Cre × Sykbfl/fl DCs show deficient cross-presentation of vaccinia antigens from infected cells. (A) Flt3L BMDCs from WT or CD11c-Cre × Sykbfl/fl mice were exposed to RAW-UV, RAW-VACV, or RAW-VACV-UV as in Figure 1. IFN-γ production was measured in CD8+ T effector cells in response to lymphoid cells of WT mice i.d. injected with WR VACV. (B) Representative set of dot plots. (C) Production of IFN-γ (mean ± SEM) from a representative experiment (n = 3 biological replicates) of 3 performed. (D–F) Lack of Syk in CD11c+ cells impairs the CD8+ T cell effector response to early and late vaccinia peptides. (D) WT or CD11c-Cre × Sykbfl/fl mice were infected i.d. in the ear with WR VACV, and 7 days later, ear dermal cell suspensions were obtained and restimulated with B8R and A3L VACV peptides. (E) Representative dot plot set. (F) Production of IFN-γ is shown as individual data from a representative experiment (n = 4 biological replicates) of 3 performed. *P < 0.05, **P < 0.01, unpaired 2-tailed Student’s t test.