The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published online November 5, 2007
doi:10.1084/jem.20071283
The Journal of Experimental Medicine, Vol. 204, No. 12, 2889-2897
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Graham et al.
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ARTICLE

 An ITAM-signaling pathway controls cross-presentation of particulate but not soluble antigens in dendritic cells

Daniel B. Graham1, Linda M. Stephenson1, Siu Kit Lam1, Karry Brim1, Hyang Mi Lee1, Jhoanne Bautista1, Susan Gilfillan1, Shreeram Akilesh1, Keiko Fujikawa2, and Wojciech Swat1

1 Department of Pathology and Immunology, Washington University School of Medicine and Siteman Cancer Center, St. Louis, MO 63110
2 Department of Pathology and Immunology, Hokkaido University School of Medicine, 060-8638 Sapporo, Japan

CORRESPONDENCE Wojciech Swat:swat{at}wustl.edu

Dendritic cells (DC) possess a unique capacity for presenting exogenous antigen on major histocompatibility class I, a process that is referred to as cross-presentation, which serves a critical role in microbial and tumor immunity. During cross-presentation, antigens derived from pathogen-infected or tumor cells are internalized and processed by DCs for presentation to cytotoxic T lymphocytes (CTLs). We demonstrate that a signaling pathway initiated by the immunoreceptor tyrosine–based activation motif (ITAM)–containing adaptors DAP12 and FcR{gamma} utilizes the Vav family of Rho guanine nucleotide exchange factors (GEFs) for processing and cross-presentation of particulate, but not soluble, antigens by DCs. Notably, this novel pathway is crucial for processing and presentation of particulate antigens, such as those associated with Listeria monocytogenes bacteria, yet it is not required for antigen uptake. Mechanistically, we provide evidence that in DCs, Vav GEFs are essential to link ITAM-dependent receptors with the activation of the NOX2 complex and production of reactive oxygen species (ROS), which regulate phagosomal pH and processing of particulate antigens for cross-presentation. Importantly, we show that genetic disruption of the DAP12/FcR{gamma}–Vav pathway leads to antigen presentation defects that are more profound than in DCs lacking NOX2, suggesting that ITAM signaling also controls cross-presentation in a ROS-independent manner.

Abbreviations used: GEF, guanine nucleotide exchange factor; ITAM, immunoreceptor tyrosine–based activation motif; LM, Listeria monocytogenes; MFI, mean fluorescence intensity; ROS, reactive oxygen species.


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