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 Blood, 15 April 2008, Vol. 111, No. 8, pp. 4245-4253.
Prepublished online as a Blood First Edition Paper on February 7, 2008; DOI 10.1182/blood-2007-03-081398.

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IMMUNOBIOLOGY

Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation and inhibits IFN-{alpha} production

Friederike Meyer-Wentrup1, Daniel Benitez-Ribas1, Paul J. Tacken1, Cornelis J. A. Punt2, Carl G. Figdor1, I. Jolanda M. de Vries1, and Gosse J. Adema1

Departments of1 Tumor Immunology and 2 Medical Oncology, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands

C-type lectin receptors (CLRs) fulfill multiple functions within the immune system by recognition of carbohydrate moieties on foreign or (altered) self-structures. CLRs on myeloid dendritic cells (DCs) have been well characterized as pattern-recognition receptors (PRRs) combining ligand internalization with complex signaling events. Much less is known about CLR expression and function in human plasmacytoid DCs (pDCs), the major type I interferon (IFN) producers. In this study, we demonstrate that, next to the CLR BDCA-2, human pDCs express DC immunoreceptor (DCIR), a CLR with putative immune-inhibitory function, but not dectin-1, mannose receptor, or DC-specific ICAM-3–grabbing nonintegrin. DCIR surface levels are reduced on pDC maturation after TLR9 triggering. Interestingly, DCIR triggering inhibits TLR9-induced IFN-{alpha} production while leaving up-regulation of costimulatory molecule expression unaffected. Furthermore, DCIR is readily internalized into pDCs after receptor triggering. We show that DCIR internalization is clathrin-dependent because it can be inhibited by hypertonic shock and dominant-negative dynamin. Importantly, antigens targeted to pDCs via DCIR are presented to T cells. These findings indicate that targeting DCIR on pDCs not only results in efficient antigen presentation but also affects TLR9-induced IFN-{alpha} production. Collectively, the data show that targeting of DCIR can modulate human pDC function and may be applied in disease preven-tion and treatment.


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