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 10

DNGR-1 deficiency blocks the secondary effector response after vaccination with the MVA virus strain.

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DNGR-1 deficiency blocks the secondary effector response after vaccinati...
(A) WT or DNGR-1–deficient mice were infected with MVA VACV and challenged 21 days later with the WR VACV strain. (B) DNGR-1 deficiency results in a higher viral load during secondary challenge following vaccination. Viral load in the ears on day 5 after secondary challenge is shown as individual data and the mean in a representative experiment of 3 performed. (C) The CD8+ T cell secondary response to early and late vaccinia peptides is defective in DNGR-1–deficient mice. Cell suspensions obtained from draining LNs on day 7 were tested against B8R and A3L VACV peptides, and the response was analyzed and depicted as in Figure 5. Results are shown from a representative experiment of 3. (D) DNGR-1 deficiency increases the lesion size upon secondary VACV challenge following MVA vaccination. Left panels show representative images at day 10 after secondary challenge. Right panel shows the temporal development of lesion size (mean ± SEM; n = 14) from a representative experiment of 3 performed. *P < 0.05, **P < 0.01, #P < 0.001, unpaired 2-tailed Student’s t test.