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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: mol.108.048769v1 74/3/896    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Marsolais, D. Articles by Rosen, H. PubMed PubMed Citation Articles by Marsolais, D. Articles by Rosen, H.

Local Not Systemic Modulation of Dendritic Cell S1P Receptors in Lung Blunts Virus-Specific Immune Responses to Influenza

Departments of Chemical Physiology and Immunology (D.M., H.R.), Chemistry (M.G., E.R.), Immunology and Microbial Sciences (K.H.E., K.B.W., M.B.A.O.), The Scripps Research Institute, La Jolla, California; Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, Missouri (B.H.); Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin (Y.H., Y.K.); and Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan (Y.K.)

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 S1P₁ receptor agonist at doses sufficient to induce systemic lymphopenia did not inhibit virus-specific T-cell response, indicating that S1P₁ 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 S1P₁ or S1P₂ on dendritic cells in the lungs after influenza virus infection.

Address correspondence to: Dr. Hugh Rosen, The Scripps Research Institute, Mail Code: ICND-118, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail: hrosen{at}scripps.edu