The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice
Santiago Zelenay, Anna M. Keller, Paul G. Whitney, Barbara U. Schraml, Safia Deddouche, Neil C. Rogers, Oliver Schulz, David Sancho, Caetano Reis e Sousa
Santiago Zelenay, Anna M. Keller, Paul G. Whitney, Barbara U. Schraml, Safia Deddouche, Neil C. Rogers, Oliver Schulz, David Sancho, Caetano Reis e Sousa
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Research Article

The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice

Abstract

DNGR-1 (CLEC9A) is a receptor for necrotic cells required by DCs to cross-prime CTLs against dead cell antigens in mice. It is currently unknown how DNGR-1 couples dead cell recognition to cross-priming. Here we found that DNGR-1 did not mediate DC activation by dead cells but rather diverted necrotic cell cargo into a recycling endosomal compartment, favoring cross-presentation to CD8+ T cells. DNGR-1 regulated cross-priming in non-infectious settings such as immunization with antigen-bearing dead cells, as well as in highly immunogenic situations such as infection with herpes simplex virus type 1. Together, these results suggest that DNGR-1 is a dedicated receptor for cross-presentation of cell-associated antigens. Our work thus underscores the importance of cross-priming in immunity and indicates that antigenicity and adjuvanticity can be decoded by distinct innate immune receptors. The identification of specialized receptors that regulate antigenicity of virus-infected cells reveals determinants of antiviral immunity that might underlie the human response to infection and vaccination.

Authors

Santiago Zelenay, Anna M. Keller, Paul G. Whitney, Barbara U. Schraml, Safia Deddouche, Neil C. Rogers, Oliver Schulz, David Sancho, Caetano Reis e Sousa

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Figure 1

DNGR-1 is required for cross-priming but not for cross-tolerance to dead cell–associated antigens.

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DNGR-1 is required for cross-priming but not for cross-tolerance to dead...
(A) WT mice were left untreated or were injected with UV-treated H-2bm1 OVA-expressing MEFs i.v. One week later mice received B16-OVA cells i.v., and the number of tumors per lung was determined after 18 days. Data are representative of 2 independent experiments (n = 6/group, each dot represents 1 mouse). (B) WT (n = 16), DNGR-1–deficient (n = 11), or IAα–/– (n = 6) mice were injected with UV-treated H-2bm1 OVA–expressing MEFs, and the percentage of H2-Kb-OVA tetramer+ cells among CD8+ T cells in blood was determined 7 days after injection. Data were pooled from 2 independent experiments; each dot represents 1 mouse. (C) WT or DNGR-1–deficient mice received CFSE-labeled CD45.1+ OT-I cells, followed by immunization with UV-treated OVA-MEFs 1 day later. Spleens were analyzed 5 days after immunization for OT-I proliferation. CFSE dilution (left panel) and total number of divided cells (right panel) are shown; each dot represents 1 mouse. (D) DNGR-1–sufficient or DNGR-1–deficient RIP-mOVA mice received CFSE-labeled CD45.1+ OT-I cells. Renal LNs were analyzed 3 days after injection for OT-I proliferation quantified by CFSE dilution (left panel) and total number of divided cells (right panel); each dot represents 1 mouse. *P < 0.05, **P < 0.01, ***P < 0.001, unpaired Student’s t test and 1-way ANOVA (Tukey’s post-test).