TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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-γ1. 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 crosslinking may be useful as a therapeutic immune modulator in human patients.

Original languageEnglish (US)
Pages (from-to)7863-7872
Number of pages10
JournalJournal of Immunology
Volume181
Issue number11
StatePublished - Dec 1 2009

Fingerprint

Myeloid Cells
Dendritic Cells
Antigens
Animal Disease Models
Type C Phospholipases
Knockout Mice
Small Interfering RNA
Immunoglobulin M
Melanoma
Neoplasms
Vaccination
Phosphorylation
T-Lymphocytes
Phenotype

ASJC Scopus subject areas

  • Immunology

Cite this

Radhakrishnan, S., Arneson, L. N., Upshaw, J. L., Howe, C. L., Felts, S. J., Colonna, M., ... Pease, L. R. (2009). TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells. Journal of Immunology, 181(11), 7863-7872.

TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells. / Radhakrishnan, Suresh; Arneson, Laura N.; Upshaw, Jadee L.; Howe, Charles L; Felts, Sara J.; Colonna, Marco; Leibson, Paul J.; Rodriguez, Moses; Pease, Larry R.

In: Journal of Immunology, Vol. 181, No. 11, 01.12.2009, p. 7863-7872.

Research output: Contribution to journalArticle

Radhakrishnan, S, Arneson, LN, Upshaw, JL, Howe, CL, Felts, SJ, Colonna, M, Leibson, PJ, Rodriguez, M & Pease, LR 2009, 'TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells', Journal of Immunology, vol. 181, no. 11, pp. 7863-7872.
Radhakrishnan S, Arneson LN, Upshaw JL, Howe CL, Felts SJ, Colonna M et al. TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells. Journal of Immunology. 2009 Dec 1;181(11):7863-7872.
Radhakrishnan, Suresh ; Arneson, Laura N. ; Upshaw, Jadee L. ; Howe, Charles L ; Felts, Sara J. ; Colonna, Marco ; Leibson, Paul J. ; Rodriguez, Moses ; Pease, Larry R. / TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells. In: Journal of Immunology. 2009 ; Vol. 181, No. 11. pp. 7863-7872.
@article{613cbfcc77294905a3be06eefb315e7a,
title = "TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells",
abstract = "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-γ1. 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 crosslinking may be useful as a therapeutic immune modulator in human patients.",
author = "Suresh Radhakrishnan and Arneson, {Laura N.} and Upshaw, {Jadee L.} and Howe, {Charles L} and Felts, {Sara J.} and Marco Colonna and Leibson, {Paul J.} and Moses Rodriguez and Pease, {Larry R}",
year = "2009",
month = "12",
day = "1",
language = "English (US)",
volume = "181",
pages = "7863--7872",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "11",

}

TY - JOUR

T1 - TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells

AU - Radhakrishnan, Suresh

AU - Arneson, Laura N.

AU - Upshaw, Jadee L.

AU - Howe, Charles L

AU - Felts, Sara J.

AU - Colonna, Marco

AU - Leibson, Paul J.

AU - Rodriguez, Moses

AU - Pease, Larry R

PY - 2009/12/1

Y1 - 2009/12/1

N2 - 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-γ1. 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 crosslinking may be useful as a therapeutic immune modulator in human patients.

AB - 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-γ1. 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 crosslinking may be useful as a therapeutic immune modulator in human patients.

UR - http://www.scopus.com/inward/record.url?scp=71849093985&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=71849093985&partnerID=8YFLogxK

M3 - Article

C2 - 19017976

AN - SCOPUS:71849093985

VL - 181

SP - 7863

EP - 7872

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 11

ER -