Two distinct activation states of plasmacytoid dendritic cells induced by influenza virus and CpG 1826 oligonucleotide

Amaya Iparraguirre^*, John W. Tobias, Scott E. Hensley^*, Katherine S. Masek, Lois L. Cavanagh^*, Michael Rendl, Christopher A. Hunter, Hildegund C. Ertl^*, Ulrich. H. von Andrian^|| and Wolfgang Weninger^*^,¶^,**^,1

^* Immunology Program, The Wistar Institute, Departments of
Penn Bioinformatics Core,
School of Veterinary Medicine,
^¶ Dermatology, and
^** Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA;
Rockefeller University, New York, New York, USA; and
^|| Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

¹ Correspondence at current address: The Centenary Institute, Locked Bag No. 6, Newtown, NSW 2042, Australia. E-mail: w.weninger{at}centenary.org.au

There is growing evidence that plasmacytoid dendritic cells(pDC) are involved in the innate recognition of various microbes.However, the precise consequences of pathogen recognition onpDC activation and function are incompletely understood. Usinga novel transgenic mouse model that facilitates the isolationof highly pure pDC populations, we found that influenza virusPR/8, a TLR7 ligand, and CpG 1826 oligonucleotide, a TLR9 ligand,induced surprisingly divergent activation programs in thesecells. pDC stimulated with PR/8 produced large amounts of typeI IFNs, and CpG 1826-stimulated pDC expressed higher levelsof costimulatory molecules and proinflammatory cytokines andinduced stronger proliferation of T cells. Transcriptome analysisuncovered the differential regulation in pDC of 178 and 1577genes by PR/8 and CpG 1826, respectively. These differencesmay relate to the activation of discrete signaling pathways,as evidenced by distinct ERK1/2 and p38 MAPK phosphorylationkinetics. Finally, pDC isolated ex vivo during PR/8 infectionor after i.v. CpG 1826 injection resembled their in vitro counterparts,corroborating that these cells can adopt specialized phenotypesin vivo. Thus, pDC display remarkable functional flexibility,which emphasizes their versatile functions in antimicrobialimmunity and inflammatory processes.

Key Words: innate immune cells • Toll-like receptors • differentiation