Extracellular mRNA induces dendritic cell activation by stimulating tumor necrosis factor-alpha secretion and signaling through a nucleotide receptor.
We previously demonstrated that dendritic cell (DC) pulsing with antigen-encoded mRNA resulted in the loading of both major histocompatibility complex class I and II antigen presentation pathways and the delivery of an activation signal. Coculture of mRNA-pulsed DC with T cells led to the induction of a potent primary immune response. DC, in addition to recognizing foreign antigens through pattern recognition receptors, also must respond to altered self, transformed, or intracellularly infected cells. This occurs through cell surface receptors that recognize products of inflammation and cell death. In this report, we characterize two signaling pathways utilized by extracellular mRNA to activate DC. In addition, a novel ligand, poly(A), is identified that mediates signaling through a receptor that can be inhibited by pertussis toxin and suramin and can be desensitized by ATP and ADP, suggesting a P2Y type nucleotide receptor. The role of this signaling activity in vaccine design and the potential effect of mRNA released by damaged cells in the induction of immune responsiveness is discussed.
Ni
Houping
H
Divisions of Infectious Diseases and Neurosurgery, University of Pennsylvania, 522B Johnson Pavilion, Philadelphia, PA 19104, USA.
Capodici
John
J
Cannon
Georgetta
G
Communi
Didier
D
Boeynaems
Jean-Marie
JM
Karikó
Katalin
K
Weissman
Drew
D
D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D012333:RNA, Messenger / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013050:Spectrometry, Fluorescence; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium