title: Local not systemic modulation of dendritic cell S1P receptors in lung blunts virus-specific immune responses to influenza.
abstract: The mechanism by which locally delivered sphingosine analogs regulate host response to localized viral infection has never been addressed. In this report, we show that intratracheal delivery of the chiral sphingosine analog (R)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol (AAL-R) or its phosphate ester inhibits the T-cell response to influenza virus infection. In contrast, neither intraperitoneal delivery of AAL-R nor intratracheal instillation of the non-phosphorylatable stereoisomer AAL-S suppressed virus-specific T-cell response, indicating that in vivo phosphorylation of AAL-R and sphingosine 1-phosphate (S1P) receptor modulation in lungs is essential for immunomodulation. Intratracheal delivery of water-soluble S1P(1) receptor agonist at doses sufficient to induce systemic lymphopenia did not inhibit virus-specific T-cell response, indicating that S1P(1) is not involved in the immunosuppressive activities of AAL-R and that immunosuppression acts independently of naive lymphocyte recirculation. Accumulation of dendritic cells (DCs) in draining lymph nodes was inhibited by intratracheal but not intraperitoneal delivery of AAL-R. Direct modulation of DCs is demonstrated by the impaired ability of virus-infected bone marrow-derived DCs treated in vitro with AAL-R to trigger in vivo T-cell response after adoptive transfer to the airways. Thus, our results suggest that locally delivered sphingosine analogs induce immunosuppression by modulating S1P receptors other than S1P(1) or S1P(2) on dendritic cells in the lungs after influenza virus infection.
authors.affiliation: Departments of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: David
authors.initials: D
authors.lastname: Marsolais
authors.forename: Bumsuk
authors.initials: B
authors.lastname: Hahm
authors.forename: Kurt H
authors.initials: KH
authors.lastname: Edelmann
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Walsh
authors.forename: Miguel
authors.initials: M
authors.lastname: Guerrero
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hatta
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.forename: Edward
authors.initials: E
authors.lastname: Roberts
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000821:virology*; D007108:Immune Tolerance / Q000187:drug effects; D009980:Influenza A virus / Q000187:drug effects; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D008216:Lymphocytic Choriomeningitis / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology*; D010766:Phosphorylation / Q000187:drug effects; D049349:Receptors, Lysosphingolipid / Q000276:immunology*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D016207:Cytokines; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine