Submitted March 21, 2007
Accepted January 31, 2008
Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation and inhibits IFN-
production
Friederike Meyer-Wentrup, Daniel Benitez-Ribas, Paul J. Tacken, Cornelis J.A. Punt, Carl G. Figdor, I. Jolanda M. de Vries, and Gosse J. Adema*
Department of Tumor Immunology, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, Netherlands
Department of Medical Oncology, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, Netherlands
* Corresponding author; email: g.adema{at}ncmls.ru.nl.
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 IFN producers. In this study, we demonstrate that next to the CLR BDCA-2, human pDCs express DCIR, a CLR with putative immune-inhibitory function, but not dectin-1, mannose receptor or DC-SIGN. DCIR surface levels are reduced upon pDC maturation following TLR9 triggering. Interestingly, DCIR triggering inhibits TLR9-induced IFN-
production, while leaving upregulation of co-stimulatory molecule expression unaffected. Furthermore, DCIR is readily internalized into pDCs after receptor triggering. We show that DCIR internalization is clathrin-dependent as 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- production. Collectively, the data show that targeting of DCIR can modulate human pDC function and may be applied in disease prevention and treatment.
