Macaque multimeric soluble CD40 ligand and GITR ligand constructs are immunostimulatory molecules in vitro

Clin Vaccine Immunol. 2006 Nov;13(11):1223-30. doi: 10.1128/CVI.00198-06. Epub 2006 Sep 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / chemical synthesis
  • Adjuvants, Immunologic / physiology*
  • Amino Acid Sequence
  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD40 Ligand / chemical synthesis
  • CD40 Ligand / physiology*
  • Cell Proliferation
  • Cells, Cultured
  • Glucocorticoid-Induced TNFR-Related Protein
  • Humans
  • Lymphocyte Culture Test, Mixed
  • Macaca mulatta
  • Mice
  • Molecular Sequence Data
  • Receptors, Nerve Growth Factor / metabolism*
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor / physiology*
  • Solubility
  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factors / genetics
  • Tumor Necrosis Factors / metabolism
  • Tumor Necrosis Factors / physiology*

Substances

  • Adjuvants, Immunologic
  • Glucocorticoid-Induced TNFR-Related Protein
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • TNFRSF18 protein, human
  • TNFSF18 protein, human
  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factors
  • CD40 Ligand

Associated data

  • GENBANK/DQ457096
  • GENBANK/DQ457097