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"INNATE SENSING OF HSV-INFECTED CELLS
BY PLASMACYTOID DENDRITIC CELLS: A
PHYSIOLOGICAL MODEL OF VIRAL RECOGNITION"

by
Richard Wnek
Molecular Pathology and Immunology Program
M.S. 2002, Seton Hall University
B.S. 2000, Seton Hall University


Thesis Advisor: Patricia Fitzgerald-Bocarsly, Ph.D.
Professor
Department of Pathology and Laboratory Medicine

Tuesday, July 26, 2011
9:30 A.M., NJDS, Room B-723


Abstract

Plasmacytoid dendritic cells (pDCs) are key regulators of antiviral immunity, linking both innate and adaptive aspects of the response, primarily via the robust production of type I interferon (IFN). They efficiently produce IFN- in response to a wide range of enveloped viruses. Unlike other IFN-producing cells, innate sensing of virus in pDCs is not dependent on direct infection, viral gene expression or the formation of replicative intermediates. Furthermore, pDCs efficiently recognize and produce type I IFNs when stimulated with virus-infected cells. Despite their seemingly weak endocytic capacity when compared to conventional dendritic cells, a mechanism must exist to capture and deliver viruses to intracellular toll-like receptors (TLRs) present in endosomes.
We hypothesize that as a professional IFN- producing cell, the pDC must have the endocytic capacity to internalize exogenously derived viral antigens without the need for direct infection or the presence of virus specific receptors expressed in target cells and tissues. From a physiological perspective, it is more likely that pDCs indirectly encounter viral antigens in the context of cells budding progeny virions or fragments of cells bearing virus particles rather than free-floating virus particles. We believe this ability to indirectly capture viral antigens from neighboring cells also confers immunological advantages to pDCs, as it serves to limit viral subversion of the host IFN response.
Using differential fluorescent labeling in a cellular co-culture model system that mimics viral recognition, the present study outlines a pDC specific, physiologically relevant, recognition mechanism that translates both in the induction of IFN- production and the subsequent maturation of pDCs into antigen presenting cells in response to indirect stimulation with HSV-infected cells. For comparison, we show how conventional peripheral blood dendritic cells differentially engage virus-infected cells in co-culture, internalize, and endosomally process virus-derived antigens.
We conclude that a divergence exists in the endocytic capacity for viral antigen uptake and endosomal processing between peripheral blood dendritic cell subsets following short-term indirect virus stimulation in co-culture. Between the subtypes, only pDCs can selectively endocytose and recognize viral antigens present in plasma membrane and cytoplasmic fragments derived from uninfected and HSV-infected cells. In addition, pDCs selectively endocytose cellular material only from viable versus apoptotic/secondary necrotic cells which may serve as an additional contextual factor in the modulation of pDC immune responses to virus-infected cells.


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