Evaluation of OX40 ligand as a costimulator of human antiviral memory CD8 T cell responses: comparison with B7.1 and 4-1BBL

J Immunol. 2005 Nov 15;175(10):6368-77. doi: 10.4049/jimmunol.175.10.6368.


CTL are important effectors of antiviral immunity. Designing adjuvants that can induce strong cytotoxic T cell responses in humans would greatly improve the effectiveness of an antiviral vaccination or therapeutic strategy. Recent evidence suggests that, in addition to its well-established role in costimulation of CD4 T cell responses, OX40L (CD134) can directly costimulate mouse CD8 T cells. In this study, we evaluated the role of OX40L in costimulation of human antiviral CD8 T cell responses and compared it with two other important costimulators, B7.1 (CD80) and 4-1BBL (CD137L). Delivery of OX40L to human monocytes using a recombinant replication-defective adenovirus led to greater expansion, up-regulation of perforin, enhanced cytolytic activity, and increased numbers of IFN-gamma- and TNF-alpha-producing antiviral memory CD8 T cells in cultures of total T cells. Synergistic or additive effects were observed when OX40L costimulation was combined with 4-1BBL (CD137L) or B7.1 (CD80) costimulation. In total T cell cultures, at low Ag dose, 4-1BBL provided the most potent costimulus for influenza-specific CD8 T cell expansion, followed by B7.1 (CD80) and then OX40L. For isolated CD8 T cells, 4-1BBL was also the most consistent costimulator, followed by B7.1. In contrast, OX40L showed efficacy in direct activation of memory CD8 T cells in only one of seven donors. Thus, OX40L costimulates human antiviral memory CD8 T cell responses largely through indirect effects and can enhance anti-influenza, anti-EBV, and anti-HIV responses, particularly in combination with 4-1BBL or B7.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand
  • Animals
  • Antigen-Presenting Cells / immunology
  • B7-1 Antigen / genetics
  • B7-1 Antigen / metabolism*
  • CD8-Positive T-Lymphocytes / immunology*
  • HIV Infections / immunology
  • Herpesvirus 4, Human / immunology
  • Humans
  • Immunologic Memory
  • In Vitro Techniques
  • Ligands
  • Lymphocyte Activation
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • OX40 Ligand
  • Orthomyxoviridae / immunology
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Necrosis Factors / genetics
  • Tumor Necrosis Factors / metabolism*


  • 4-1BB Ligand
  • B7-1 Antigen
  • Ligands
  • Membrane Glycoproteins
  • OX40 Ligand
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • TNFRSF4 protein, human
  • TNFSF4 protein, human
  • TNFSF9 protein, human
  • Tnfrsf4 protein, mouse
  • Tnfsf9 protein, mouse
  • Tumor Necrosis Factors