16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

COMPARATIVE EVALUATION OF CD70, LIGHT AND 4-1BBL, AS COSTIMULATORS OF HUMAN ANTI-VIRAL MEMORY CD8 T CELLS

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThAa0104

Wang C., Wen T., Watts T.
University of Toronto, Department of Immunology, Toronto, Canada

BACKGROUND: An effective HIV vaccine adjuvant is needed, capable of inducing strong cytotoxic T cell responses. The TNF family member 4-1BBL has been shown to play a key role in CD8 T cell responses. Dual costimulation of 4-1BBL and B7 can directly expand HIV-specific CD8 T cells, increase perforin production on a per cell basis and enhance cytolytic function in chronic HIV-infected people. 4-1BBL is found in a gene cluster with two other costimulatory TNF family ligands, CD70 and LIGHT. In this study we compared the efficacy of the three costimulatory ligands in activation of human anti-viral memory CD8 T cells.

METHODS: Purified CD8 T cells from donors were stimulated in vitro with autologous monocytes infected with replication defective adenoviruses carrying 4-1BBL, CD70, LIGHT or an empty vector.

RESULTS: As expected from previous studies, 4-1BBL enhanced expansion of Ag-specific CD8 T cells in nearly all donors tested. In contrast, only 50% of healthy donors tested directly responded to CD70 even at high influenza peptide concentration. None of the donors tested responded to LIGHT. For donors that showed a response to both CD70 and 4-1BBL, CD137L was most effective at low peptide concentration in directly expanding Ag-specific memory CD8 T cells, up-regulating perforin production, and enhancing cytolytic function. However in the responding donors at optimal antigen dose, CD70 was particularly efficacious in inducing CD8s to produce multiple cytokines.

CONCLUSIONS: Thus, three costimulatory molecules from the same gene cluster have different impact on anti-viral memory CD8 response in human and CD70 and 4-1BBL represent a promising adjuvant combination for expanding CD8 effector cells. This work was funded by the Canadian Institutes of Health Research and by CANVAC, the Canadian Network for Vaccines and Immunotherapeutics.

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2006-08-13
ThAa0104

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