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.
View: Text | PDF
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

×

Figure 4

Lack of DNGR-1 blocks cross-presentation of VACV antigens in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Lack of DNGR-1 blocks cross-presentation of VACV antigens in vivo. (A) R...
(A) RAW cells were infected with WR VACV and UV treated to inactivate the virus (RAW-VACV-UV) and then transferred i.p. (107 cells per mouse) to WT and Clec9agfp/gfp mice. (B and C) Absence of DNGR-1 impairs the CD8+ effector T cell response to cross-presented VACV peptides. After 6 days, peritoneal cells were extracted and restimulated with B8R or A3L VACV peptides. (B) Representative dot plot set. (C) Absolute numbers of IFN-γ–producing CD8+ T cells found in peritoneal washes, shown as individual data from a representative experiment (n = 4 biological replicates) of 3 performed. (D and E) Lack of DNGR-1 reduces CTL killing activity in vivo against cross-presented vaccinia peptides. On day 5 after transfer, splenocytes from syngeneic mice were loaded with the early peptide B8R or the late peptide A3L (CFSElo or CellTraceVioletlo, respectively) or no peptide (CFSEhi or CellTraceViolethi) and transferred i.p. The peritoneal lavage was analyzed 16 hours later for specific killing of targets. (D) Representative histogram set. Control histograms from noninfected mice show the proportion of transferred targets. (E) Percentage specific killing in a representative experiment of 3 performed. Data are presented as mean ± SEM (n = 4 biological replicates). **P < 0.01, #P < 0.001, unpaired 2-tailed Student’s t test.