title: Absence of vasoactive intestinal peptide expression in hematopoietic cells enhances Th1 polarization and antiviral immunity in mice.
abstract: Vasoactive intestinal peptide (VIP) induces regulatory dendritic cells (DC) in vitro that inhibit cellular immune responses. We tested the role of physiological levels of VIP on immune responses to murine CMV (mCMV) using VIP-knockout (VIP-KO) mice and radiation chimeras engrafted with syngenic VIP-KO hematopoietic cells. VIP-KO mice had less weight loss and better survival following mCMV infection compared with wild-type (WT) littermates. mCMV-infected VIP-KO mice had lower viral loads, faster clearance of virus, with increased numbers of IFN-γ(+) NK and NKT cells, and enhanced cytolytic activity of NK cells. Adaptive antiviral cellular immunity was increased in mCMV-infected VIP-KO mice compared with WT mice, with more Th1/Tc1-polarized T cells, fewer IL-10(+) T cells, and more mCMV-M45 epitope peptide MHC class I tetramer(+) CD8(+) T cells (tetramer(+) CD8 T cells). mCMV-immune VIP-KO mice had enhanced ability to clear mCMV peptide-pulsed target cells in vivo. Enhanced antiviral immunity was also seen in WT transplant recipients engrafted with VIP-KO hematopoietic cells, indicating that VIP synthesized by neuronal cells did not suppress immune responses. Following mCMV infection there was a marked upregulation of MHC-II and CD80 costimulatory molecule expression on DC from VIP-KO mice compared with DC from WT mice, whereas programmed death-1 and programmed death ligand-1 expression were upregulated in activated CD8(+) T cells and DC, respectively, in WT mice, but not in VIP-KO mice. Because the absence of VIP in immune cells increased innate and adaptive antiviral immunity by altering costimulatory and coinhibitory pathways, selective targeting of VIP signaling represents an attractive therapeutic target to enhance antiviral immunity.
authors.affiliation: Department of Hematology/Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Li
authors.forename: Lauren
authors.initials: L
authors.lastname: Southerland
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Hossain
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Giver
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Kasia
authors.initials: K
authors.lastname: Darlak
authors.forename: Wayne
authors.initials: W
authors.lastname: Harris
authors.forename: James
authors.initials: J
authors.lastname: Waschek
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000473:pathology; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000473:pathology; D006566:Herpesviridae Infections / Q000276:immunology* / Q000517:prevention & control*; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007117:Immunization, Secondary; D016130:Immunophenotyping; D008088:Listeriosis / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000276:immunology*; D011828:Radiation Chimera; D018417:Th1 Cells / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D014660:Vasoactive Intestinal Peptide / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
chemical_list: D014660:Vasoactive Intestinal Peptide