title: Macaque multimeric soluble CD40 ligand and GITR ligand constructs are immunostimulatory molecules in vitro.
abstract: CD40 ligand (CD40L) and GITR ligand (glucocorticoid-induced tumor necrosis factor receptor-related protein ligand [GITRL]) are tumor necrosis factor superfamily molecules that can be used as vaccine adjuvants. In a previous human immunodeficiency virus (HIV) DNA vaccine study in mice, we found that plasmids expressing multimeric soluble forms of trimeric CD40L (i.e., many trimers) were stronger activators of CD8(+) T-cell responses than were single-trimer soluble forms or the natural membrane-bound molecule. This report describes similar multimeric soluble molecules that were constructed for studies in macaques. Both two-trimer and four-trimer forms of macaque CD40L were active in B-cell proliferation assays using macaque and human cells. With human cells, four-trimer macaque GITRL costimulated CD4(+) T-cell proliferation and abrogated the immunosuppressive effects of CD4(+) CD25(+) regulatory T cells on a mixed leukocyte reaction. These molecular adjuvants provide new tools for vaccine development in the simian immunodeficiency virus system and other macaque models.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093-0679, USA.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Stone
authors.forename: Suzanne
authors.initials: S
authors.lastname: Barzee
authors.forename: Victoria
authors.initials: V
authors.lastname: Snarsky
authors.forename: Celsa A
authors.initials: CA
authors.lastname: Spina
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Vinod Kumar Bhaskara
authors.initials: VK
authors.lastname: Pillai
authors.forename: Rama Rao
authors.initials: RR
authors.lastname: Amara
authors.forename: François
authors.initials: F
authors.lastname: Villinger
authors.forename: Richard S
authors.initials: RS
authors.lastname: Kornbluth
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000138:chemical synthesis / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D008253:Macaca mulatta; D051379:Mice; D008969:Molecular Sequence Data; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human; C478967:TNFSF18 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D023201:CD40 Ligand