TREM-2 Mediated Signaling Induces Antigen Uptake and Retention in Mature Myeloid Dendritic Cells1

• Published in: The Journal of immunology (1950) 2008-12, Vol.181 (11), p.7863-7872
• Main Authors: Radhakrishnan, Suresh, Arneson, Laura N., Upshaw, Jadee L., Howe, Charles L., Felts, Sara J., Colonna, Marco, Leibson, Paul J., Rodriguez, Moses, Pease, Larry R.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606

This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI) . The American Association of Immunologists, Inc. (AAI), the publisher of The JI , holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI ; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org . Myeloid dendritic cells (mDC) activated with a B7-DC-specific cross-linking IgM antibody (B7-DC XAb) take up and retain antigen and interact with T cell compartments to affect a number of biologic changes that together cause strong anti-tumor responses and blockade of inflammatory airway disease in animal models. The molecular events mediating the initial responses in mDC remain unclear. Here we show that B7-DC XAb caused rapid phosphorylation of the adaptor protein DAP12 and intracellular kinases Syk and PLCγ1. Pretreatment of mDC with the Syk inhibitor Piceatannol blocked B7-DC XAb-induced antigen uptake with a concomitant loss of tumor protection in mice. Vaccination with tumor lysate-pulsed wildtype mDC XAb , but not TREM-2 knockout mDC XAb , protected mice from lethal melanoma challenge. Multi-molecular caps appeared within minutes of B7-DC XAb binding to either human or mouse mDC, and FRET analysis showed that class II, CD80, CD86 and TREM-2 are recruited in tight association on the cell surface. When TREM-2 expression was reduced in WT mDC using shRNA or by using mDC from TREM-2 knockout mice, in vitro DC failed to take up antigen after B7-DC XAb stimulation. These results directly link TREM-2 signaling with one change in the mDC phenotype that occurs in response to this unique antibody. The parallel signaling events observed in both human and mouse mDC support the hypothesis that B7-DC cross-linking may be useful as a therapeutic immune modulator in human patients.