Evaluation of OX40 Ligand as a Costimulator of Human Antiviral Memory CD8 T Cell Responses: Comparison with B7.1 and 4-1BBL

• Published in: Journal of Immunology Vol. 175; no. 10; pp. 6368 - 6377
• Main Authors: Serghides, Lena, Bukczynski, Jacob, Wen, Tao, Wang, Chao, Routy, Jean-Pierre, Boulassel, Mohamed-Rachid, Sekaly, Rafick-Pierre, Ostrowski, Mario, Bernard, Nicole F, Watts, Tania H
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-11-2005
• Subjects: 4-1BB Ligand; Adenovirus; Animals; Antigen-Presenting Cells - immunology; B7-1 Antigen - genetics; B7-1 Antigen - metabolism; CD8-Positive T-Lymphocytes - immunology; Herpesvirus 4, Human - immunology; HIV Infections - immunology; Human immunodeficiency virus; Humans; Immunologic Memory; In Vitro Techniques; Ligands; Lymphocyte Activation; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Orthomyxoviridae - immunology; OX40 Ligand; 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
• ISSN: 0022-1767; 1550-6606; 1365-2567
• 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.