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

Suresh Radhakrishnan^*, Laura N. Arneson^*, Jadee L. Upshaw^*, Charles L. Howe^*,, Sara J. Felts^*, Marco Colonna, Paul J. Leibson^*, Moses Rodriguez^*, and Larry R. Pease^2,*

^* Department of Immunology, Department of Neurology, College of Medicine, Mayo Clinic, Rochester, MN 55905; and Pathology and Immunology Program, Washington University School of Medicine, St. Louis, MO 63110

Myeloid dendritic cells (mDC) activated with a B7-DC-specific cross-linking IgM Ab (B7-DC XAb) take up and retain Ag and interact with T cell compartments to affect a number of biologic changes that together cause strong antitumor responses and blockade of inflammatory airway disease in animal models. The molecular events mediating the initial responses in mDC remain unclear. In this study we show that B7-DC XAb caused rapid phosphorylation of the adaptor protein DAP12 and intracellular kinases Syk and phospholipase C-1. Pretreatment of mDC with the Syk inhibitor piceatannol blocked B7-DC XAb-induced Ag uptake with a concomitant loss of tumor protection in mice. Vaccination with tumor lysate-pulsed wild-type B7-DC XAb-activated mDC, but not TREM-2 knockout XAb-activated mDC, protected mice from lethal melanoma challenge. Multimolecular 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 wild-type mDC using short hairpin RNA or by using mDC from TREM-2 knockout mice, in vitro DC failed to take up Ag 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 Ab. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants R01 CA104996-4 (to L.R.P.), R01 HL077296-3 (to L.R.P.), and R01 CA96859 (to L.R.P.) from the National Institutes of Health and by a grant from the Ralph Wilson Medical Research Foundation.

² Address correspondence and reprint requests to Dr. Larry R. Pease, Department of Immunology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail address: pease.larry{at}mayo.edu

³ Abbreviations used in this paper: DC, dendritic cell; mDC, myeloid DC; poly(I:C), polyinosinic-polycytidylic acid; XAb, cross-linking Ab; PLC, phospholipase C; shRNA, short hairpin RNA.