krn-7000 and Virus-Diseases

The nonpolymorphic CD1 molecules present lipid antigens to T cells. In myeloid DC humans express five different CD1 proteins (CD1a-e; the corresponding CD1 genes are designated CD1A-E). A role for CD1d-restricted NKT cells in the control of virus infections has been delineated from clinical observations, mouse models and viral evasion mechanisms targeting CD1d. How NKT cells are activated by virus infections is unclear. We found that human myeloid DC differentially regulate CD1 antigen presentation in response to viral danger signals. Stimulation with type I IFN, viral TLR ligands or viruses strongly enhanced the number of CD1D transcripts in human myeloid DC but diminished the abundance of CD1A, CD1B and CD1E mRNA. These changes on the transcriptional level were mirrored by altered cellular distribution and increased surface expression of CD1d. As a consequence NKT cells were activated and showed a Th1-like response. Moreover, NKT cell activation in PBMC exposed to viral danger signals was dependent on human plasmacytoid DC which produce large amounts of IFN-alpha. In conclusion, our data indicate that viral danger signals trigger NKT cell activation by enhancing CD1d de novo synthesis through increasing the abundance of CD1D mRNA in human myeloid DC.

Topics: Aminoquinolines; Antigen Presentation; Antigens, CD1; Antigens, CD1d; Cell Line; Cell Membrane; Coculture Techniques; Cytomegalovirus; Dendritic Cells; Galactosylceramides; Gene Expression; Herpesvirus 1, Human; Humans; Imiquimod; Interferon Inducers; Interferon Type I; Interferon-alpha; Interferon-gamma; Intracellular Space; Killer Cells, Natural; Leukocytes, Mononuclear; Lymphocyte Activation; Poly I-C; Toll-Like Receptors; Virus Diseases

A critical component of the host's innate immune response involves lipid Ag presentation by CD1d molecules to NK T cells. In this study we used murine CD1d1-transfected L (L-CD1) cells to study the effect of viruses on CD1d-mediated Ag presentation to NKT cells and found that an infection with vesicular stomatitis and vaccinia (but not lymphocytic choriomeningitis) virus inhibited murine CD1d1-mediated Ag presentation. This was under the reciprocal control of the MAPKs, p38 and ERK, and was due to changes in the intracellular trafficking of CD1d1. The reciprocal regulation of CD1d1-mediated Ag presentation by MAPK suggests that the targeting of these pathways is a novel means of immune evasion by viruses.

Topics: Animals; Antigen Presentation; Antigens, CD1; Antigens, CD1d; Cell Line; Extracellular Signal-Regulated MAP Kinases; Galactosylceramides; Killer Cells, Natural; Lymphocytic choriomeningitis virus; Mice; p38 Mitogen-Activated Protein Kinases; Protein Transport; T-Lymphocyte Subsets; Vaccinia virus; Vesicular stomatitis Indiana virus; Virus Diseases