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* Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, University Medical Centre, Nijmegen, The Netherlands;
Department of Hematology, Oncology and Immunology, University of Tübingen, Tübingen, Germany; and
Leucocyte Membrane Protein Laboratory, Austin Research Institute, Heidelberg, Australia
C-type lectins are pattern-recognition receptors important for pathogen binding and uptake by APCs. Evidence is accumulating that integration of incoming cellular signals in APCs is regulated by grouping of receptors and signaling molecules into organized membrane complexes, such as lipid rafts and tetraspanin microdomains. In this study, we demonstrate that C-type lectin dectin-1 functionally interacts with leukocyte-specific tetraspanin CD37. Dectin-1 and CD37 colocalize on the surface of human APCs. Importantly, macrophages of CD37-deficient (CD37–/–) mice express decreased dectin-1 membrane levels, due to increased dectin-1 internalization. Furthermore, transfection of CD37 into a macrophage cell line elevated endogenous dectin-1 surface expression. Although CD37 deficiency does not affect dectin-1-mediated phagocytosis, we observed a striking 10-fold increase of dectin-1-induced IL-6 production in CD37–/– macrophages compared with wild-type cells, despite reduced dectin-1 cell surface expression. Importantly, the observed increase in IL-6 production was specific for dectin-1, because signaling via other pattern-recognition receptors was unaffected in CD37–/– macrophages and because the dectin-1 ligand curdlan was used. Taken together, these findings show that tetraspanin CD37 is important for dectin-1 stabilization in APC membranes and controls dectin-1-mediated IL-6 production.
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1 This work was supported in part by the Dutch Cancer Association (Koningin Wilhelmina Fonds Fellowship to A.B.v.S.), by the Deutsche Forschungsgemeinschaft (Grant ME 2051/2-1 to F.M.-W.), and by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (ZonMw 912-02-034 to G.J.A.).
2 Address correspondence and reprint requests to Prof. Gosse J. Adema, Department of Tumor Immunology, Radboud University Medical Centre, Nijmegen, Nijmegen Centre for Molecular Life Sciences/278 TIL, Post Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail address: g.adema{at}ncmls.ru.nl
3 Abbreviations used in this paper: DC, dendritic cell; PRR, pattern-recognition receptor; PAMP, pathogen-associated molecular pattern; IP, immunoprecipitation; co-IP, coimmunoprecipitation; EGFP, enhanced GFP; WT, wild type; HA, hemagglutinin.
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