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, … , David Sancho, Caetano Reis e Sousa
Santiago Zelenay, … , David Sancho, Caetano Reis e Sousa
Published April 16, 2012
Citation Information: J Clin Invest. 2012;122(5):1615-1627. https://doi.org/10.1172/JCI60644.
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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 3

DNGR-1 regulates MHC class I cross-presentation but not MHC class II presentation of dead cell–associated antigens.

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DNGR-1 regulates MHC class I cross-presentation but not MHC class II pre...
(A) The adjuvanticity of dead cells is independent of DNGR-1. Purified CD8α+-like Flt3L-BMDCs from WT or DNGR-1–deficient (Clec9agfp/gfp) mice were pulsed with 1 pM SIINFEKL peptide, washed, and cultured with UV-treated H-2bm1 MEFs and CFSE-labeled OT-I T cells. OT-I proliferation was quantified after 3 days. (B and C) DNGR-1 regulates cross-presentation of dead cell–associated antigens. Purified CD8α+-like Flt3L-BMDCs from WT or DNGR-1–deficient mice were cultured with UV-treated OVA-MEFs or latex beads coated with OVA (OVA beads). Proliferation of CFSE-labeled OT-I (B) or OT-II (C) T cells was quantified on day 3 or 5 (respectively) of coculture with DCs. (D) Purified CD8α+-like Flt3L-BMDCs from WT, DNGR-1–deficient, or Tap1–/– mice were cultured with UV-treated OVA-MEFs and B3Z cells. NFAT reporter activity in B3Z cells was measured using a colorimetric assay after 24 hours of coculture. Results are mean ± sd and representative of at least 3 independent experiments. *P < 0.05, **P < 0.01, unpaired Student’s t test.