Enhancement of HIV-specific CD8 T cell responses by dual costimulation with CD80 and CD137L

Jacob Bukczynski, Tao Wen, Chao Wang, Natasha Christie, Jean Pierre Routy, Mohamed Rachid Boulassel, Colin M. Kovacs, Kelly S. MacDonald, Mario Ostrowski, Rafick Pierre Sekaly, Nicole F. Bernard, Tania H. Watts

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

HIV-specific CD8 T cell responses are defective in chronic HIV infection. In this study, we report that costimulation with either CD137L (4-1BBL) or CD80 (B7.1) enhanced the Ag-specific expansion and acquisition of elector Function by HIV-specific memory CD8 T cells. Ag-specific T cells from recently infected donors showed maximal expansion with single costimulatory molecules. Dual costimulation of T cells from recently infected donors or from healthy donors responding to influenza epitopes led to enhanced responses when the accumulation of cytokines was measured. However, accumulation of regulatory cytokines, particularly IFN-γ led to inhibition of further Ag-specific CD8 T cell expansion in the cultures. This inhibition was relieved by neutralization of IFN-γ or of IFN-γ, TNF, and IL-10. Thus, strong costimulation of T cells in vitro can lead to induction of regulatory cytokines at levels that limit further T cell expansion. In marked contrast, T cells from long-term (>4 years) infected HIV+ donors exhibited reduced Ag-specific CD8 T cell expansion, reduced CD4 T cell responses, and minimal cytokine accumulation. Deal costimulation with both 4-1BBL and B7.1 enhanced responses of T cells from long-term infected subjects to a level similar to that obtained with T cells from early in HIV infection. Experiments with purified CD8 T cells showed that B7.1 and 4-1BBL could act directly and synergistically on CD8 T cells. Taken together, these data suggest that 4-1BBL and B7.1 have additive or synergistic effects on HIV-specific CD8 T cell responses and represent a promising combination for therapeutic vaccination for HIV.

Original languageEnglish
Pages (from-to)6378-6389
Number of pages12
JournalJournal of Immunology
Volume175
Issue number10
Publication statusPublished - Nov 15 2005

    Fingerprint

ASJC Scopus subject areas

  • Immunology

Cite this

Bukczynski, J., Wen, T., Wang, C., Christie, N., Routy, J. P., Boulassel, M. R., ... Watts, T. H. (2005). Enhancement of HIV-specific CD8 T cell responses by dual costimulation with CD80 and CD137L. Journal of Immunology, 175(10), 6378-6389.